Lymphopoiesis
Encyclopedia
Lymphopoiesis refers to the generation of lymphocyte
s, one of the five different types of white blood cells (WBC), and is also more formally called lymphoid
hematopoiesis.
lineage as opposed to other lineages of blood cells such as the myeloid
lineage and the erythroid lineage.
Nomenclature, the problem of naming things properly, is not trivial in this case because lymphocytes - which are certainly found in blood and originate along with blood cells in the bone marrow of the adult - are almost by definition also strongly associated with lymph fluid and a separate connective system, the lymphatic system, which is assuredly not the blood system. Connected to, parallel to and interacting with and feeding into the blood system, yes, but easily distinguished apart by any scientific observer.
Lymphopoiesis is now used interchangeably with the term "lymphocytopoiesis" - the making of lymphocytes - but other sources may distinguish between the two, stating that "lymphopoiesis" additionally refers to creating lymphatic tissue, while "lymphocytopoiesis" refers only to the creation of cells in that tissue. It is rare now for lymphopoiesis to refer to the creation of lymphatic tissues.
Myelopoiesis
refers to 'generation of cells of the myeloid lineage' and erythropoiesis
refers to 'generation of cells of the erythroid lineage' etc., so parallel usage has evolved in which lymphopoiesis refers to 'generation of cells of the lymphoid lineage'.
Observations on research going back well over 100 years had elucidated the two great classes of WBC - Myeloid and Lymphoid - and great advances in medicine and science have resulted from these studies. It was only natural to ask where these two great classes of cells arose, and after much work two cell types with some strong stem cell
properties were isolated and defined - CMP, the common myeloid progenitor and CLP, the common lymphoid progenitor for mice. But science is an additive game and it was eventually found these progenitors were not unique, and further that the two great families of Myeloid and Lymphoid were not disjoint, but rather two partially interwoven family trees. This is more than just nomenclature, it is new science that provides challenges of complexity yet offers new vistas of bio-science and the promise of early enhancement of private and public health issues. And it gives insight into the nature of redundancy and overlap in the immune system and hints how to use this to advantage.
(CLPs) in mice. Were this system to fail, the body would be largely undefended from infection.
The set comprising CLP cells and similar progenitors are themselves descendants of the pluripotential hemopoietic stem cell
(pHSC) which is capable of generating all of the cell types of the complete blood cell system. Despite their remarkable ability to generate the complete suite of lymphocytes, most progenitors are not true stem cells, however, and must be continually renewed by differentiation from the pHSC stem cell.
Many progenitor cells are also referred to as transit cells, sometimes also called transit amplifying cells, the meaning of this term being that the transit cell may found a new sub-lineage but the number of resultant cells is strictly limited (although possibly very large, even trillions yet finite) and the lineage is terminated by cells that die off (by apoptosis
) or remain as cells that can no longer divide. Examples of such cells are CFUs (Colony-forming units - referred to as such because of their ability to form colonies in vitro in artificial media) such as CFU-T.
In mice, transplantation of a single pHSC cell can reconstitute a sub-lethally irradiated host (i.e. a mouse that has been irradiated so that all leukocytes are killed) with all these lineages of cells, including all types of lymphocytes via CLPs. This has been known for more than 40 years.
Lymphopoiesis continues throughout life and so progenitor cells and their parent stem cells must always be present.
and enter the fetus to provide some protection against pathogen
s, and also leukocytes that come from breast milk and enter circulation via the digestive tract.
However early in gestation
the developing embryo has begun its own lymphopoiesis from the fetal liver. Lymphopoiesis also arises from the yolk sac
. This is in contrast to the adult where all lymphocytes originate in the bone marrow.
There are four major types of lymphocytes, many sub-types, and hundreds or thousands of lymphocyte cell types that have been identified by scientists. All are generated by normal or abnormal lymphopoiesis except for certain artificial strains created in the laboratory by development from existing strains. Although lymphocytes are usually considered mature (as seen in blood tests) they are certainly not inert but can and do get around the body to anywhere there is a need; and when such need arises, new rounds of 'downstream' lymphopoiesis such as cell multiplication and differentiation may arise, coupled with intense mitotic and metabolic activity.
This is hardly a simple topic. In his 1976 text Immunology, Aging and Cancer immunologist and Nobel Prize winner Sir Frank Macfarlane Burnet speculated that the immune system might one day be found to be as complex as the nervous system. As the production of lymphocytes is so close to the central role of the immune response it is wise to approach the study of it with some humility in the face of the task, although there are general principles that help in understanding.
Lymphopoiesis can be viewed in a mathematical sense as a recursive process of cell division and also as a process of differentiation, measured by changes to the properties of cells.
Considering the P as the ‘mother’ cell, but not a true stem cell, it may divide into two new cells, which are themselves identical, but differ to some degree from the mother. Or the mother cell P may divide unequally into two new daughter cells both of which differ from each other and also from the mother.
Any daughter cell will usually have new specialized abilities and if it is able to divide it will form a new sub-lineage. The difference of a daughter cell from the mother may be great, but it could also be much less, even subtle. What the P mother cell does not do is divide into two new P mother cells or a mother and a daughter; this is a matter of observation as such limited progenitor cells are known to not self-renew.
T and B lymphocytes are indistinguishable histologically
（that is, under a light microscope they cannot be told apart.）Indeed, the inactive B and T cells are so featureless with few cytoplasmic organelle
s and mostly inactive chromatin
that until the 1960s textbooks could describe these cells, now the central focus of immunology, as having no known function!!
However T and B lymphocytes are very distinct cell lineages and they ‘grow up’ in different places in the body. They perform quite different (although co-operative) functions in the body. No evidence has ever been found that T and B cells can ever interconvert. T and B cells are biochemically distinct and this is reflected in the differing markers and receptors they possess on their cell surfaces. This seems to be true in all vertebrates, although there are many differences in the details between the species.
then migrate to the cortex of the thymus
to undergo maturation in an antigen-free environment for about one week where a mere 2-4% of the T cells succeed. The remaining 96-98% of T cells die by apoptosis
and are phagocytosed by macrophages in the thymus. So many thymocytes (T cells) die during the maturation process because there is intensive screening to make sure each thymocyte has the ability to recognize self-peptide:self-MHC complex
and for self tolerance. The apoptosed thymocyte dies a willing and noble death and it is quickly recycled.
Upon maturity, there are several forms of thymocytes including
When T-Cells become activated
they undergo a further series of developments. A small, resting T lymphocyte rapidly undergoes blastogenic transformation into a large lymphocyte (13–15μm). This large lymphocyte (known in this context as a lymphoblast
) then divides several times to produce an expanded population of medium (9–12μm) and small lymphocytes (5–8μm) with the same antigenic specificity. Final activated and differentiated T lymphocytes are once again morphologically
indistinguishable from a small, resting lymphocyte. Thus the following developmental states may be noticed in sequence in blood tests:
Basic Map of T Cell lymphopoiesis
This basic map of T Cell formation, in sequence, is simplified and is akin to textbook descriptions, and may not reflect latest research.(Medical Immunology, p. 119)
In the thymus
In the Periphery
T cells are unique among the lymphocyte populations in their ability to further specialize as mature cells and become yet more mature. And T Cells come in many flavors, for example: the conventional TcRαβ T cells; the so-called unconventional TcRγδ T cells; NKT cells; and T regulatory cells (Treg). Details regarding the developmental and life cycle of the unconventional T cells are less well-described compared to the conventional T cells.
Stages of T cell maturation
Stage One: Thymic Migration
Multipotent lymphoid progenitors (MLP) enter the T cell pathway as they immigrate to the thymus. The most primitive cells in the thymus are the early thymocyte progenitors (ETP), which retain all lymphoid and myeloid potential but exist only transiently, rapidly differentiating into T and NK lineages. (Medical Immunology, p. 118)
Stage Two: Proliferative Expansion and T Lineage Commitment
Final commitment to the T cell lineage occurs within the thymic microenvironment, the microscopic structures of the thymus where T cells are nurtured. The most primitive T cells retain pluripotential ability and can differentiate into cells of the myeloid or lymphoid lineages (B cells, DC, T cells, or NK cells).
More differentiated double negative T cells (DN2 cells) have more limited potentiality but are not yet fully restricted to the T cell lineage (they can still develop into DC, T cells, or NK cells). Later on, they are fully committed to the T cell lineage- when thymoctyes expressing Notch1 receptors engage thymic stromal cells expressing Notch1 ligands, the thymocytes become finally committed to the T-cell lineage. See Gallery Image “Double Negatives”
With the commitment to the T cell lineage, begins a very complex process known as TcR
gene rearrangement. This creates an enormous diversity of T cells bearing antigen receptors. Afterward some T cells leave the thymus to migrate to the skin and mucosae.
Stage Three: β-Selection
Stage Four: T Cell Receptors Selection
Only 2% to 3% of the differentiating thymocytes, those that express TcR capable of interaction with MHC molecules, but tolerant to self-peptides, survive the Stage Four selection process.
Stage Five: Continuing Differentiation in the Periphery
It was previously believed that the human thymus remained active as the site of T cell differentiation only until early adulthood and that later in adult life the thymus atrophies, perhaps even vanishing. Recent reports indicate that the human thymus is active throughout adult life. Thus several factors may contribute to the supply of T cells in adult life: generation in the thymus, extra-thymic differentiation, and the fact that memory T cells are long-lived and survive for decades.
The thymus also gives rise to the so-called ‘unconventional T cells’ such at γδ T cells, Natural Killer T cells (NKT) and regulatory T cells (Treg).
γδT cells represent only 1% to 5% of the circulating T cells, but are abundant in the mucosal immune system and the skin, where they represent the dominant T cell population. These ‘non-MHC restricted T cells’ are involved in specific primary immune responses, tumor surveillance, immune regulation and wound healing.
Several differences between αβ and γδ T cell development have been described. They emigrate from the thymus in “waves” of clonal populations, which home to discrete tissues. For example, one kind is found in the peripheral blood while another predominates in the intestinal tract.
Human NKT cells are a unique population and are thought to play an important role in tumor immunity and immunoregulation.
"Tregs" are considered as naturally occurring regulatory T cells. Tregs comprised about 5% of the circulating CD4+ T cells. These cells are thought to possess important an autoimmunity property by regulating 'autoreactive' T cells in the periphery. (Medical Immunology, p. 117-122)
It is a good mnemonic aide that B cells are formed in the bone marrow, but it is a mere coincidence since B cells were first studied in the chicken's bursa of Fabricius
and it is from this bursa that B cells get their name.
These B cells then leave the bone marrow and migrate to peripheral lymphoid tissues, such as a lymph node. Once in a secondary lymphoid organ the B cell can be introduced to an antigen that it is able to recognize.
Through this antigen recognition and other cell interactions the B cell becomes activated and then divides and differentiates to become a plasma cell. The plasma cell, a B cell end product, is a very active antibody
-secreting cell that helps protect the body by attacking and binding to antigen.
Even after many decades of research, some controversy remains as to where B cells mature and 'complete their education', with the possibility remaining that the site may also partially be peri-intestinal lymphoid tissues
.
B lymphopoiesis occurs exclusively in the bone marrow and B lymphocytes are made continuously throughout life there in a 'microenvironment' composed of stromal cells, extracellular matrix
, cytokines and growth factors, which are critical for proliferation, differentiation, and survival of early lymphocyte and B-lineage precursors.
The relative proportion of precursor B cells in the bone marrow remains rather constant throughout the life span of an organism. There are stages such as Pre-B-I cells (5% to 10% of the total); Pre-B-II cells (60% to 70%) while the remaining 20% to 25% are immature B cells. Most textbooks say that B Cells mature in the bone marrow but, generally, immature B cells migrate to the spleen for 'higher education' of some sort where they go through transitional stages before final maturation.(Medical Immunology, p. 136)
B lymphocytes are identified by the presence of soluble immunoglobulin G
(IgG). This is the most common protective immunoglobulin in the adult body. After antigenic stimulation, B cells differentiate into plasma cells that secrete large quantities of soluble IgG. This is the final stage of B lymphopoiesis but it is the clincher because the plasma cells must either issue antibody close to a source of infection, or disseminate it in the blood to fight an infection at a distance or in an inaccessible part of the body.
Basic map of B cell lymphopoiesis
A generally regarded valid map of B cell lymphopoiesis is as follows in sequence, in two parts with the first being in the bone marrow and the second in the spleen:. The development process in the bone marrow occurs in Germinal Centers
.
In the bone marrow
In the spleen
or virally-infected cells. It is well-known that lymphocytes never have granules or at least not granules that are readily visible even upon staining. Everyone knows this, but NK cells are the exception. They do have numerous granules which provide their ability to kill cells and these granules are why NK cells have an alternate name, LGL, Large Granular Lymphocytes.
NK cells not only have a catchy movie-title name (Natural Killer) but are also the only lymphocytes considered part of the innate immune system
(in contrast to the adaptive immune system
. Yet they are much more closely related to T cells (part of the adaptive immune system
) than to other cells of the innate immune system. NK cells not only share many surface markers, functions and activities in common with T Cells, they also arise from a common T/NK progenitor. The T/NK precursor is also believed to be the source of a subpopulation of lymphoid DC. (Medical Immunology, p. 121)
NK cells have a definition 'barcode' as CD3, CD16+, CD56t lymphocytes. (See Barcode Section of this article). NK progenitors can be found mainly in the thymus (mouse), but the thymus is not absolutely required for NK development. Probably NK cells can develop in a variety of organs but the major site of NK cell development is not known.
In humans, the majority (85–90%) of the NK cells have a high cytolytic capacity (the ability to lyse
cells). A smaller subset (10–15%) called NK 'CD56 bright' is chiefly responsible for cytokine
production and has enhanced survival. Traveling to lymph nodes the 'CD56 bright' NK cells differentiate again into mature NK cells which express killer cell immunoglobulin-like receptors
(KIR), natural cytotoxicity receptors (NCR), and critical adhesion molecules. (Medical Immunology, p. 122)
DCs are highly specialized and efficient antigen-presenting cells. Cells identical in appearance come both from a myeloid lineage (referred to as myeloid dendritic cells) and also from a lymphoid lineage (referred to as plasmacytoid dendritic cells).
The development and regulation of DC is not well-characterized. While the DC precursors have been identified in the human fetal liver, thymus, and bone marrow, during adult life DC are thought to be produced only from the bone marrow and released into the blood to wander and settle down. Overall a large number of DC of varying types are dispatched throughout the body, especially at epithelia such as skin, to monitor invaders and nibble their antigens. (Medical Immunology, p. 122)
Killers are distinguished from cells such as macrophages that eat other cells or munch debris by a method called phagocytosis. Killers do not use phagocytosis, they just kill and leave the clean-up to other cells.
Killers are known to attack virus-infected cells and cells that have become cancerous. Because of these abilities much research has been done into transforming these qualities into medical therapy but progress has been slow.
Here is the parade of killers and how they work:
(also called Tc or antigen-specific cytolytic T lymphocytes (CTL)). Tc kill by apoptosis and either splash their target with perforin
or granzymes or else use Fas-Fasl Interaction to command target elimination. This kills cells that are infected and display antigen.
These kill with exactly the same methods as Tc, but have no interaction with any antigen. They select their targets based on typical molecules displayed by cells that are under stress by viral infection. NK Cells mainly are in the circulation (5-15% of the circulating lymphocytes) yet are also distributed in tissues everywhere.
Natural Killer T Cells. Human NK T cells are a unique population (which express NK cell markers such as CD56 and KIR). NKT cells are thought to play an important role in tumor immunity and immunoregulation. (Medical Immunology, p. 135), yet little is known. Recent evidence suggests a role working together with hepatic stellate cell
s being a liver-resident antigen-presenting cell that presents lipid antigens to and stimulates proliferation of NKT cells.
A heterogeneous group with ill-defined properties.
However in summary there is no known cell or set of cells that is capable of killing cancerous cells in general.
Because all WBCs are microscopic, colorless and often seemingly identical in appearance they are individually identified by their natural chemical markers, many of which have been analyzed and named. When two cells have the same markers, the reasonable assumption is made that the cells are identical at that time. A set of markers is colloquially describes as the barcode for that cell or that cell line.
HSC are technically described as: lacking FMS-like tyrosine kinase3 (Flt3) and lacking the markers specific to discrete lymphoid lineages (Lin), but expressing high levels of Sca1 and c-kit; HSC also express CD44, low levels of Thy1.1 (CD90), but no IL-7Ra or CD27.
This is called the (surface) phenotype of an HSC. It can be expressed as a set (Lin2, Sca1high, c-kit high, CD44+, Thy1.1low, CD27 2, and IL-7Ra2). This set is a ‘barcode’ for the HSC, akin to the barcode label attached to your chicken-wing plastic bag for checkout at a supermarket! Scientists use these barcodes to check, categorize and accumulate cells for many purposes often using laboratory methods such as cell flow cytometry
. These barcodes partially define the modern meaning of phenotype
for leukocytes.
Progression of HSC differentiation and lineage commitment is indicated by changes in this phenotype
. That is, as the cell changes, the markers will also change and the barcode will change.
for questions. For example it was thought that the process of lymphopoiesis was a direct, orderly unidirectional sequence. But it is not clear if end-stage lymphocytes come from progenitors that are homogeneous populations or overlapping populations. Nor is it clear whether lineages of lymphocytes develop via a continuum of differentiation with a progressive loss of lineage options or whether abrupt events result in the acquisition of certain properties.
Changes in cytoplasm, morphology
of the cell nucleus, granules, cell internal biochemistry, signaling molecules and cell surface markers are difficult to correlate with definite stages in lymphopoiesis. The morphological differences don't just correspond to steps in mitosis
(somatic cell division), but result from continuous “maturation processes”of the cell nucleus as well as of the cytoplasm and so one must not be too rigid about morphological distinctions between certain cell stages.
Until recently the model of the CMP generating all myeloid cell and the CLP generating all lymphoid cells was considered necessary and sufficient to explain the known facts observed in the generation of WBCs, and it is still found in most basic textbooks. However beginning around 2000 and gaining momentum after 2005 in both studies on man and mouse, new complexities were noted and published in papers. These studies are important now mainly to immunology researchers but are likely to eventually lead to changes in medical treatments.
The changes were sparked by observations that lymphopoiesis did not always break into two lineages at the level of the CLP. Worse, some macrophages (long considered a myeloid lineage) could be generated by lymphoid lineage progenitors. In essence focus has been shifted away from the CLP to the MLP (lymphoid-specified progenitors), which are clearly lymphoid progenitors yet retain some myeloid potential, particularly the interesting ability in both man and mouse to make macrophages - one of the most versatile of immune cell defenders - and also many dendritic cells, the best 'watchdogs' of antigen invaders.
pHSC, MPP and ELP cells are not fully committed to the lymphoid lineage because if one is removed to a different location it may differentiate into non-lymphoid progeny. However CLP are committed to the lymphoid lineage. The CLP is the transit cell responsible for these (generally parallel) stages of development, below:
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s, one of the five different types of white blood cells (WBC), and is also more formally called lymphoid
Lymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
hematopoiesis.
The name Lymphopoiesis
Lymphocytes are considered to be of the lymphoidLymphoid
Lymphoid is a term used to describe lymph or the lymphatic system.In the context of lymphoid leukemia, it refers specifically to lymphocytes Lymphoid leukemias and lymphomas are now considered to be tumors of the same type of cell lineage. They are called "leukemia" when in the blood or marrow and...
lineage as opposed to other lineages of blood cells such as the myeloid
Myeloid
The term myeloid suggests an origin in the bone marrow or spinal cord, or a resemblance to the marrow or spinal cord.In hematopoiesis, the term "myeloid cell" is used to describe any leukocyte that is not a lymphocyte...
lineage and the erythroid lineage.
Lymphopoiesis is now used interchangeably with the term "lymphocytopoiesis" - the making of lymphocytes - but other sources may distinguish between the two, stating that "lymphopoiesis" additionally refers to creating lymphatic tissue, while "lymphocytopoiesis" refers only to the creation of cells in that tissue. It is rare now for lymphopoiesis to refer to the creation of lymphatic tissues.
Myelopoiesis
Myelopoiesis
Myelopoiesis is the regulated formation of myeloid cells, including eosinophilic granulocytes, basophilic granulocytes, neutrophilic granulocytes, and monocytes...
refers to 'generation of cells of the myeloid lineage' and erythropoiesis
Erythropoiesis
Erythropoiesis is the process by which red blood cells are produced. It is stimulated by decreased O2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin...
refers to 'generation of cells of the erythroid lineage' etc., so parallel usage has evolved in which lymphopoiesis refers to 'generation of cells of the lymphoid lineage'.
Observations on research going back well over 100 years had elucidated the two great classes of WBC - Myeloid and Lymphoid - and great advances in medicine and science have resulted from these studies. It was only natural to ask where these two great classes of cells arose, and after much work two cell types with some strong stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
properties were isolated and defined - CMP, the common myeloid progenitor and CLP, the common lymphoid progenitor for mice. But science is an additive game and it was eventually found these progenitors were not unique, and further that the two great families of Myeloid and Lymphoid were not disjoint, but rather two partially interwoven family trees. This is more than just nomenclature, it is new science that provides challenges of complexity yet offers new vistas of bio-science and the promise of early enhancement of private and public health issues. And it gives insight into the nature of redundancy and overlap in the immune system and hints how to use this to advantage.
The purpose of Lymphopoiesis
The complete loss of or loss of function of any WBC cell type is a serious health matter, but lymphopoiesis is absolutely necessary for life. Mature lymphocytes are a critical part of the immune system that (with the exception of memory B and T cells) have short lives measured in days or weeks and must be continuously generated throughout life by cell division and differentiation from cells such as common lymphoid progenitorsProgenitor cell
A progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target" cell...
(CLPs) in mice. Were this system to fail, the body would be largely undefended from infection.
The set comprising CLP cells and similar progenitors are themselves descendants of the pluripotential hemopoietic stem cell
Pluripotential hemopoietic stem cell
Hematopoietic stem cells , also spelled Hæmatopoietic stem cells, are multipotent stem cells that give rise to all the blood cell types from the myeloid , and lymphoid lineages...
(pHSC) which is capable of generating all of the cell types of the complete blood cell system. Despite their remarkable ability to generate the complete suite of lymphocytes, most progenitors are not true stem cells, however, and must be continually renewed by differentiation from the pHSC stem cell.
Many progenitor cells are also referred to as transit cells, sometimes also called transit amplifying cells, the meaning of this term being that the transit cell may found a new sub-lineage but the number of resultant cells is strictly limited (although possibly very large, even trillions yet finite) and the lineage is terminated by cells that die off (by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
) or remain as cells that can no longer divide. Examples of such cells are CFUs (Colony-forming units - referred to as such because of their ability to form colonies in vitro in artificial media) such as CFU-T.
In mice, transplantation of a single pHSC cell can reconstitute a sub-lethally irradiated host (i.e. a mouse that has been irradiated so that all leukocytes are killed) with all these lineages of cells, including all types of lymphocytes via CLPs. This has been known for more than 40 years.
Lymphopoiesis continues throughout life and so progenitor cells and their parent stem cells must always be present.
Overview of Lymphopoiesis
In the case of mammals such as man lymphopoiesis begins with limited passive provision by the mother of lymphocytes and substantial immunoglobulin G that cross the placentaPlacenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and enter the fetus to provide some protection against pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s, and also leukocytes that come from breast milk and enter circulation via the digestive tract.
However early in gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
the developing embryo has begun its own lymphopoiesis from the fetal liver. Lymphopoiesis also arises from the yolk sac
Yolk sac
The yolk sac is a membranous sac attached to an embryo, providing early nourishment in the form of yolk in bony fishes, sharks, reptiles, birds, and primitive mammals...
. This is in contrast to the adult where all lymphocytes originate in the bone marrow.
There are four major types of lymphocytes, many sub-types, and hundreds or thousands of lymphocyte cell types that have been identified by scientists. All are generated by normal or abnormal lymphopoiesis except for certain artificial strains created in the laboratory by development from existing strains. Although lymphocytes are usually considered mature (as seen in blood tests) they are certainly not inert but can and do get around the body to anywhere there is a need; and when such need arises, new rounds of 'downstream' lymphopoiesis such as cell multiplication and differentiation may arise, coupled with intense mitotic and metabolic activity.
This is hardly a simple topic. In his 1976 text Immunology, Aging and Cancer immunologist and Nobel Prize winner Sir Frank Macfarlane Burnet speculated that the immune system might one day be found to be as complex as the nervous system. As the production of lymphocytes is so close to the central role of the immune response it is wise to approach the study of it with some humility in the face of the task, although there are general principles that help in understanding.
The process of Lymphopoiesis
| Lymphopoiesis Acronyms |
|---|
| • B-NK Progenitor for B and NK |
| • CB Cord blood |
| • CFU Colony-forming Unit |
| • CLP Common Lymphoid Progenitor |
| • CMP Common Myeloid Progenitor |
| • DC Dendritic Cell (Myeloid or Lymphoid) |
| • ELP Early Lymphoid Progenitors |
| • ETP the most primitive cells in the thymus are the Early Thymocyte Progenitors |
| • G-CSF Granulocyte Colony Stimulating Factor |
| • GM-CSF Granulocyte Macrophage Colony Stimulating Factor |
| • GMP Granulocyte Macrophage Progenitor; |
| • HSC pluripotential Hemopoietic Stem Cell |
| • MDC combined Macrophage and DC progenitor potential |
| • MEP megakaryocytic and erythroid progenitor |
| • MLP Multi-lymphoid Progenitor potential, any progenitor minimally able to give rise to B cells, T cells and NK cells |
| • MPP Multipotent Progenitor |
| • Notch Notch signaling pathway re T Cell commitment from progenitors |
| [ edit ] |
Lymphopoiesis can be viewed in a mathematical sense as a recursive process of cell division and also as a process of differentiation, measured by changes to the properties of cells.
- Given that lymphocytes arise from specific types of limited stem cells - which we can call P (for Progenitor) cells - such cells can divide in several ways. These are general principles of limited stem cells.
Considering the P as the ‘mother’ cell, but not a true stem cell, it may divide into two new cells, which are themselves identical, but differ to some degree from the mother. Or the mother cell P may divide unequally into two new daughter cells both of which differ from each other and also from the mother.
Any daughter cell will usually have new specialized abilities and if it is able to divide it will form a new sub-lineage. The difference of a daughter cell from the mother may be great, but it could also be much less, even subtle. What the P mother cell does not do is divide into two new P mother cells or a mother and a daughter; this is a matter of observation as such limited progenitor cells are known to not self-renew.
- There is a sort of exception when daughter cells at some level of the lineage may divide several times to form more seemingly identical cells, but then further differentiation and division will inevitably occur, until a final stage is reached in which no further division can occur and the cell type lineage is finally mature. An example of maturity is a plasma cell, from the B cell lineage, which produces copious antibody, but cannot divide and eventually dies after a few days or weeks.
- The progenitor CLP of the mouse or the progenitor MLP of the human differentiates into lymphocytes by first becoming a lymphoblast (Medical Immunology, p. 10). It then divides several more times to become a prolymphocyte that has specific cell-surface markers unique to either a (1) T cellT cellT cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
or (2) B cellB cellB cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
. The progenitor can also differentiate into (3) natural killer cellNatural killer cellNatural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
s (NK) and (4) dendritic cellDendritic cellDendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s.
- T Cells, B Cells and NK Cells are unique to the lymphocyte family, but dendritic cells are not. Dendritic cells of identical appearance but different markers are spread throughout the body, and come from either lymphoid and myeloid lineages, but these cells may have somewhat different tasks and may take up lodging preferentially in different locations. (Revise in light of new research) This is now an open question; also, the different dendritic cell lineages may have different ‘tasks’ and stay in different ‘locations.’
T and B lymphocytes are indistinguishable histologically
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
（that is, under a light microscope they cannot be told apart.）Indeed, the inactive B and T cells are so featureless with few cytoplasmic organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s and mostly inactive chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
that until the 1960s textbooks could describe these cells, now the central focus of immunology, as having no known function!!
However T and B lymphocytes are very distinct cell lineages and they ‘grow up’ in different places in the body. They perform quite different (although co-operative) functions in the body. No evidence has ever been found that T and B cells can ever interconvert. T and B cells are biochemically distinct and this is reflected in the differing markers and receptors they possess on their cell surfaces. This seems to be true in all vertebrates, although there are many differences in the details between the species.
- Regardless of whether the CLP (mouse) or MLP or a small closely related set of progenitor cells take credit for generating the profusion of lymphocytes, it remains an interesting observation that the same lymphoid progenitors can still opt to generate some cells that are clearly identifiably myeloid.
Lymphopoiesis for T cells
T cells are formed in bone marrowBone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
then migrate to the cortex of the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
to undergo maturation in an antigen-free environment for about one week where a mere 2-4% of the T cells succeed. The remaining 96-98% of T cells die by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and are phagocytosed by macrophages in the thymus. So many thymocytes (T cells) die during the maturation process because there is intensive screening to make sure each thymocyte has the ability to recognize self-peptide:self-MHC complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
and for self tolerance. The apoptosed thymocyte dies a willing and noble death and it is quickly recycled.
Upon maturity, there are several forms of thymocytes including
- T-helperT helper cellT helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
(needed for activation of other cells such as B cells and macrophages), - T-cytotoxicCytotoxic T cellA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
(which kill virally-infected cells), - T-memory (T cells that remember antigens previously encountered), and
- T-suppressor cellsRegulatory T cellRegulatory T cells , sometimes known as suppressor T cells, are a specialized subpopulation of T cells which suppresses activation of the immune system and thereby maintains tolerance to self-antigens. The existence of regulatory T cells was the subject of significant controversy among...
(which moderate the immune response of other leukocytes). Also called T-regulatory Cell, or just ‘Treg(s)’, to be cool.
When T-Cells become activated
Immunologic activation
In immunology, activation is the transition of leucocytes and other cell types involved in the immune system. On the other hand, deactivation is the transition in the reverse direction...
they undergo a further series of developments. A small, resting T lymphocyte rapidly undergoes blastogenic transformation into a large lymphocyte (13–15μm). This large lymphocyte (known in this context as a lymphoblast
Lymphoblast
Lymphoblasts are immature cells which typically differentiate to form mature lymphocytes. Normally lymphoblasts are found in the bone marrow, but in acute lymphoblastic leukemia , lymphoblasts proliferate uncontrollably and are found in large numbers in the peripheral blood.The size is between 10...
) then divides several times to produce an expanded population of medium (9–12μm) and small lymphocytes (5–8μm) with the same antigenic specificity. Final activated and differentiated T lymphocytes are once again morphologically
Morphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
indistinguishable from a small, resting lymphocyte. Thus the following developmental states may be noticed in sequence in blood tests:
- Prolymphocyte
- Large lymphocyte
- Small lymphocyte
Basic Map of T Cell lymphopoiesis
This basic map of T Cell formation, in sequence, is simplified and is akin to textbook descriptions, and may not reflect latest research.(Medical Immunology, p. 119)
In the thymus
- MLP
- ETP
- DN1
- (B; Mφ)
- DN2
- (DC; NK)
- DN3
- (γδ)
- DN4
- DP
- (TNK; CD4; CD8; Treg)
In the Periphery
- (Th1; Th2)
More details on T Lymphopoiesis
Unlike other lymphoid lineages, T cell development occurs almost exclusively in the thymus. T-lymphopoiesis does not occur automatically but requires signals generated from the thymic stromal cells. The process has an astonishingly complex beauty to it. Several stages at which specific regulators and growth factors are required for T cell development to proceed have been defined. Interestingly, later in T cell development and its maturation these same regulatory factors again are used to influence T cell specialization.T cells are unique among the lymphocyte populations in their ability to further specialize as mature cells and become yet more mature. And T Cells come in many flavors, for example: the conventional TcRαβ T cells; the so-called unconventional TcRγδ T cells; NKT cells; and T regulatory cells (Treg). Details regarding the developmental and life cycle of the unconventional T cells are less well-described compared to the conventional T cells.
Stages of T cell maturation
Stage One: Thymic Migration
Multipotent lymphoid progenitors (MLP) enter the T cell pathway as they immigrate to the thymus. The most primitive cells in the thymus are the early thymocyte progenitors (ETP), which retain all lymphoid and myeloid potential but exist only transiently, rapidly differentiating into T and NK lineages. (Medical Immunology, p. 118)
Stage Two: Proliferative Expansion and T Lineage Commitment
Final commitment to the T cell lineage occurs within the thymic microenvironment, the microscopic structures of the thymus where T cells are nurtured. The most primitive T cells retain pluripotential ability and can differentiate into cells of the myeloid or lymphoid lineages (B cells, DC, T cells, or NK cells).
More differentiated double negative T cells (DN2 cells) have more limited potentiality but are not yet fully restricted to the T cell lineage (they can still develop into DC, T cells, or NK cells). Later on, they are fully committed to the T cell lineage- when thymoctyes expressing Notch1 receptors engage thymic stromal cells expressing Notch1 ligands, the thymocytes become finally committed to the T-cell lineage. See Gallery Image “Double Negatives”
With the commitment to the T cell lineage, begins a very complex process known as TcR
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
gene rearrangement. This creates an enormous diversity of T cells bearing antigen receptors. Afterward some T cells leave the thymus to migrate to the skin and mucosae.
Stage Three: β-Selection
Stage Four: T Cell Receptors Selection
Only 2% to 3% of the differentiating thymocytes, those that express TcR capable of interaction with MHC molecules, but tolerant to self-peptides, survive the Stage Four selection process.
Stage Five: Continuing Differentiation in the Periphery
It was previously believed that the human thymus remained active as the site of T cell differentiation only until early adulthood and that later in adult life the thymus atrophies, perhaps even vanishing. Recent reports indicate that the human thymus is active throughout adult life. Thus several factors may contribute to the supply of T cells in adult life: generation in the thymus, extra-thymic differentiation, and the fact that memory T cells are long-lived and survive for decades.
Even more details
- Unconventional T cells
The thymus also gives rise to the so-called ‘unconventional T cells’ such at γδ T cells, Natural Killer T cells (NKT) and regulatory T cells (Treg).
- γδ T cells
γδT cells represent only 1% to 5% of the circulating T cells, but are abundant in the mucosal immune system and the skin, where they represent the dominant T cell population. These ‘non-MHC restricted T cells’ are involved in specific primary immune responses, tumor surveillance, immune regulation and wound healing.
Several differences between αβ and γδ T cell development have been described. They emigrate from the thymus in “waves” of clonal populations, which home to discrete tissues. For example, one kind is found in the peripheral blood while another predominates in the intestinal tract.
- Natural Killer T cells
Human NKT cells are a unique population and are thought to play an important role in tumor immunity and immunoregulation.
- T Regulatory cells
"Tregs" are considered as naturally occurring regulatory T cells. Tregs comprised about 5% of the circulating CD4+ T cells. These cells are thought to possess important an autoimmunity property by regulating 'autoreactive' T cells in the periphery. (Medical Immunology, p. 117-122)
Lymphopoiesis for B cells
B cells are formed and mature in bone marrow (and spleen).It is a good mnemonic aide that B cells are formed in the bone marrow, but it is a mere coincidence since B cells were first studied in the chicken's bursa of Fabricius
Bursa of Fabricius
In birds, the bursa of Fabricius is the site of hematopoiesis, a specialized organ that, as first demonstrated by Bruce Glick and later by Max Cooper and Robert Good, is necessary for B cell development in birds...
and it is from this bursa that B cells get their name.
These B cells then leave the bone marrow and migrate to peripheral lymphoid tissues, such as a lymph node. Once in a secondary lymphoid organ the B cell can be introduced to an antigen that it is able to recognize.
Through this antigen recognition and other cell interactions the B cell becomes activated and then divides and differentiates to become a plasma cell. The plasma cell, a B cell end product, is a very active antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-secreting cell that helps protect the body by attacking and binding to antigen.
Even after many decades of research, some controversy remains as to where B cells mature and 'complete their education', with the possibility remaining that the site may also partially be peri-intestinal lymphoid tissues
Gut-associated lymphoid tissue
The digestive tract's immune system is often referred to as gut-associated lymphoid tissue and works to protect the body from invasion. GALT is an example of mucosa-associated lymphoid tissue.-Function:...
.
B lymphopoiesis occurs exclusively in the bone marrow and B lymphocytes are made continuously throughout life there in a 'microenvironment' composed of stromal cells, extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
, cytokines and growth factors, which are critical for proliferation, differentiation, and survival of early lymphocyte and B-lineage precursors.
The relative proportion of precursor B cells in the bone marrow remains rather constant throughout the life span of an organism. There are stages such as Pre-B-I cells (5% to 10% of the total); Pre-B-II cells (60% to 70%) while the remaining 20% to 25% are immature B cells. Most textbooks say that B Cells mature in the bone marrow but, generally, immature B cells migrate to the spleen for 'higher education' of some sort where they go through transitional stages before final maturation.(Medical Immunology, p. 136)
B lymphocytes are identified by the presence of soluble immunoglobulin G
Immunoglobulin G
Immunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...
(IgG). This is the most common protective immunoglobulin in the adult body. After antigenic stimulation, B cells differentiate into plasma cells that secrete large quantities of soluble IgG. This is the final stage of B lymphopoiesis but it is the clincher because the plasma cells must either issue antibody close to a source of infection, or disseminate it in the blood to fight an infection at a distance or in an inaccessible part of the body.
Basic map of B cell lymphopoiesis
A generally regarded valid map of B cell lymphopoiesis is as follows in sequence, in two parts with the first being in the bone marrow and the second in the spleen:. The development process in the bone marrow occurs in Germinal Centers
Germinal center
Germinal centers are sites within lymph nodes where mature B lymphocytes rapidly proliferate, differentiate, mutate their antibodies , and class switch their antibodies during a normal immune response to an infection...
.
In the bone marrow
- Pro-B
- Pre-B-I
- Pre-B-II large
- Pre-B-II small
- Imm(ature)
In the spleen
- T1
- T2/T3
- (Marginal Zone (MZ); B-1 ; B-2)
- B-2 further differentiate into:
- (Germinal Center (GC); Memory ; Plasma )
Lymphopoiesis for NK cells
NK cells, which lack antigen specific receptors, develop in the bone marrow. After maturation and release from the marrow they circulate in the blood through their lifetime seeking opportunity. The opportunity they seek is to encounter and recognize and then kill abnormal cells such as cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
or virally-infected cells. It is well-known that lymphocytes never have granules or at least not granules that are readily visible even upon staining. Everyone knows this, but NK cells are the exception. They do have numerous granules which provide their ability to kill cells and these granules are why NK cells have an alternate name, LGL, Large Granular Lymphocytes.
NK cells not only have a catchy movie-title name (Natural Killer) but are also the only lymphocytes considered part of the innate immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
(in contrast to the adaptive immune system
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
. Yet they are much more closely related to T cells (part of the adaptive immune system
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
) than to other cells of the innate immune system. NK cells not only share many surface markers, functions and activities in common with T Cells, they also arise from a common T/NK progenitor. The T/NK precursor is also believed to be the source of a subpopulation of lymphoid DC. (Medical Immunology, p. 121)
NK cells have a definition 'barcode' as CD3, CD16+, CD56t lymphocytes. (See Barcode Section of this article). NK progenitors can be found mainly in the thymus (mouse), but the thymus is not absolutely required for NK development. Probably NK cells can develop in a variety of organs but the major site of NK cell development is not known.
In humans, the majority (85–90%) of the NK cells have a high cytolytic capacity (the ability to lyse
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
cells). A smaller subset (10–15%) called NK 'CD56 bright' is chiefly responsible for cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
production and has enhanced survival. Traveling to lymph nodes the 'CD56 bright' NK cells differentiate again into mature NK cells which express killer cell immunoglobulin-like receptors
Killer-cell immunoglobulin-like receptor
Killer-cell immunoglobulin-like receptors , are a family of cell surface proteins found on important cells of the immune system called natural killer cells. They regulate the killing function of these cells by interacting with MHC class I molecules, which are expressed on all cell types...
(KIR), natural cytotoxicity receptors (NCR), and critical adhesion molecules. (Medical Immunology, p. 122)
Lymphopoiesis for dendritic cells
Dendritic cell is usually abbreviated DC or DCs. The process by which CLP cells may differentiate to generate dendritic cells of lymphoid lineage is not yet well defined.DCs are highly specialized and efficient antigen-presenting cells. Cells identical in appearance come both from a myeloid lineage (referred to as myeloid dendritic cells) and also from a lymphoid lineage (referred to as plasmacytoid dendritic cells).
The development and regulation of DC is not well-characterized. While the DC precursors have been identified in the human fetal liver, thymus, and bone marrow, during adult life DC are thought to be produced only from the bone marrow and released into the blood to wander and settle down. Overall a large number of DC of varying types are dispatched throughout the body, especially at epithelia such as skin, to monitor invaders and nibble their antigens. (Medical Immunology, p. 122)
Comparison of Killers from Lymphopoiesis
Lymphocytes have a number of alarming properties such as the ability to wander around the body and take up lodging almost anywhere, and while on the way issue commands in the form of cytokines and chemokines and lymphokines, commands that affect many cell types in the body and which may also recursively induce further lymphopoiesis. One strong behavior pattern that captivates researchers and the public alike is the ability of lymphocytes to act as police, judge and executioner to kill other cells or demand that they suicide, a command that is usually obeyed. There seems to be no other sentencing option available.Killers are distinguished from cells such as macrophages that eat other cells or munch debris by a method called phagocytosis. Killers do not use phagocytosis, they just kill and leave the clean-up to other cells.
Killers are known to attack virus-infected cells and cells that have become cancerous. Because of these abilities much research has been done into transforming these qualities into medical therapy but progress has been slow.
Here is the parade of killers and how they work:
- Cytotoxic T cells
(also called Tc or antigen-specific cytolytic T lymphocytes (CTL)). Tc kill by apoptosis and either splash their target with perforin
Perforin
Perforin-1 is a protein that in humans is encoded by the PRF1 gene.- Function :Perforin is a cytolytic protein found in the granules of CD8 T-cells and NK cells. Upon degranulation, perforin inserts itself into the target cell's plasma membrane, forming a pore. The lytic membrane-inserting part...
or granzymes or else use Fas-Fasl Interaction to command target elimination. This kills cells that are infected and display antigen.
- NK cells (also called LGL (large granular lymphocytes))
These kill with exactly the same methods as Tc, but have no interaction with any antigen. They select their targets based on typical molecules displayed by cells that are under stress by viral infection. NK Cells mainly are in the circulation (5-15% of the circulating lymphocytes) yet are also distributed in tissues everywhere.
- LAK cells (Lymphokine-activated killer) are a laboratory/clinical subset of NK Cells promoted by IL-2 to attack tumor cells.
- NKT cells see Natural Killer T cellNatural Killer T cellNatural killer T cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self- and foreign lipids and glycolipids...
main article
Natural Killer T Cells. Human NK T cells are a unique population (which express NK cell markers such as CD56 and KIR). NKT cells are thought to play an important role in tumor immunity and immunoregulation. (Medical Immunology, p. 135), yet little is known. Recent evidence suggests a role working together with hepatic stellate cell
Hepatic stellate cell
Hepatic stellate cells , also known as perisinusoidal cells or Ito cells , are pericytes found in the perisinusoidal space of the liver also known as the space of Disse...
s being a liver-resident antigen-presenting cell that presents lipid antigens to and stimulates proliferation of NKT cells.
- Natural killer-like T cells
A heterogeneous group with ill-defined properties.
However in summary there is no known cell or set of cells that is capable of killing cancerous cells in general.
Labeling Lymphopoiesis
Because all WBCs are microscopic, colorless and often seemingly identical in appearance they are individually identified by their natural chemical markers, many of which have been analyzed and named. When two cells have the same markers, the reasonable assumption is made that the cells are identical at that time. A set of markers is colloquially describes as the barcode for that cell or that cell line.
- Here is an example of how a barcode can come to be, for the all-important HSC as an example.
HSC are technically described as: lacking FMS-like tyrosine kinase3 (Flt3) and lacking the markers specific to discrete lymphoid lineages (Lin), but expressing high levels of Sca1 and c-kit; HSC also express CD44, low levels of Thy1.1 (CD90), but no IL-7Ra or CD27.
This is called the (surface) phenotype of an HSC. It can be expressed as a set (Lin2, Sca1high, c-kit high, CD44+, Thy1.1low, CD27 2, and IL-7Ra2). This set is a ‘barcode’ for the HSC, akin to the barcode label attached to your chicken-wing plastic bag for checkout at a supermarket! Scientists use these barcodes to check, categorize and accumulate cells for many purposes often using laboratory methods such as cell flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
. These barcodes partially define the modern meaning of phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
for leukocytes.
Progression of HSC differentiation and lineage commitment is indicated by changes in this phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
. That is, as the cell changes, the markers will also change and the barcode will change.
- Typical barcodes for some cell types appearing in this article.
| Cell Type | Barcode |
|---|---|
| ETP | C-Kit+, CD44+, CD25- |
| DN1 | CD44+, CD25- |
| DN2 | CD44+, CD25+ |
- Note explaining the barcode parameter details: Flt3 is a cytokine tyrosine kinase receptor thought to be important in early lymphoid development. In addition, Flt3 plays a major role in maintaining B lymphoid progenitors. CD27 plays a role in lymphoid proliferation, differentiation, and apoptosis. The acquisition of CD27 and Flt3 by the HSC coincides with the loss of long-term repopulating potential. At this stage the cells retain both lymphoid and myeloid potential and are referred to as multipotent progenitors. (Medical Immunology, p. 114)
Developing our knowledge of Lymphopoiesis
Remember that immunology is a developing field. New questions emerge in immunology continuously as though there were a stem cellStem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
for questions. For example it was thought that the process of lymphopoiesis was a direct, orderly unidirectional sequence. But it is not clear if end-stage lymphocytes come from progenitors that are homogeneous populations or overlapping populations. Nor is it clear whether lineages of lymphocytes develop via a continuum of differentiation with a progressive loss of lineage options or whether abrupt events result in the acquisition of certain properties.
Changes in cytoplasm, morphology
Morphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
of the cell nucleus, granules, cell internal biochemistry, signaling molecules and cell surface markers are difficult to correlate with definite stages in lymphopoiesis. The morphological differences don't just correspond to steps in mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
(somatic cell division), but result from continuous “maturation processes”of the cell nucleus as well as of the cytoplasm and so one must not be too rigid about morphological distinctions between certain cell stages.
- Models and updates on the Lymphopoiesis family tree
Until recently the model of the CMP generating all myeloid cell and the CLP generating all lymphoid cells was considered necessary and sufficient to explain the known facts observed in the generation of WBCs, and it is still found in most basic textbooks. However beginning around 2000 and gaining momentum after 2005 in both studies on man and mouse, new complexities were noted and published in papers. These studies are important now mainly to immunology researchers but are likely to eventually lead to changes in medical treatments.
The changes were sparked by observations that lymphopoiesis did not always break into two lineages at the level of the CLP. Worse, some macrophages (long considered a myeloid lineage) could be generated by lymphoid lineage progenitors. In essence focus has been shifted away from the CLP to the MLP (lymphoid-specified progenitors), which are clearly lymphoid progenitors yet retain some myeloid potential, particularly the interesting ability in both man and mouse to make macrophages - one of the most versatile of immune cell defenders - and also many dendritic cells, the best 'watchdogs' of antigen invaders.
In brief
However, whatever the details may turn out to be, the process of lymphopoiesis always seems to relentlessly give rise to progeny with special attributes and abilities - 'superpowers' so to speak - but with progressively more restricted lymphoid developmental potential.The old model: Lymphoid vs Myeloid
This model of lymphopoiesis had the virtue of relative simplicity, agreement with nomenclature and terminology, and is essentially valid for the favorite lab animal, the mouse.- pHSC pluripotent, self-renewing, hematopoietic stem cells which give rise to
- MPP multipotent progenitors, which give rise to
- ELP (or PRO) Prolymphocytes, early lymphoid progenitors, and finally to the
- CLP Common lymphoid progenitor, a cell type fully committed to the lymphoid lineage.
pHSC, MPP and ELP cells are not fully committed to the lymphoid lineage because if one is removed to a different location it may differentiate into non-lymphoid progeny. However CLP are committed to the lymphoid lineage. The CLP is the transit cell responsible for these (generally parallel) stages of development, below:
- NK cells
- Dendritic cells (lymphoid lineage; DC2 )
- Progenitor B cells
- Pro-B cells => Early Pro (or pre-pre)-B cells => Late Pro (or pre-pre)-B cells
- Large Pre-B cells => Small Pre-B cells
- Immature B cells
- B Cells => (B1 cells; B2 cells)
- Plasma cells
- Pro-T cells
- T-cells
Research on new models
- The Common Myelolymphoid Progenitor: A Key Intermediate Stage in Hemopoiesis Generating T and B Cells
- Identification of Flt3 + Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential: A Revised Road Map for Adult Blood Lineage Commitment
- Adult T-cell progenitors retain myeloid potential
- Research Findings May Shed Light on T-cell Leukemias and Immunodeficiencies
- Blood Lines Redrawn
- The earliest thymic progenitors for T cells possess myeloid lineage potential
- Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development
- Not a split decision for human hematopoiesis
General immunology reference texts
Texts in bold are the most heavily cited in this article.- Cell Communication in Nervous and Immune System; Gundelfinger, Seidenbecher, Schraven; Springer Berlin Heidelberg New York; 2006; ISBN 3-540-36828-0
- Color Atlas of Hematology; Theml et al; Thieme; 2004; ISBN 1-58890-193-9
- Dynamics of Cancer; Steven A. Frank; Princeton University Press, Princeton, New Jersey; 2007; ISBN 0–691–13365–2, Creative Commons Public License
- Fundamental Immunology, 5th edition; William E. Paul (Editor); Lippincott Williams & Wilkins Publishers; 2003; ISBN 0-7817-3514-9
- Immuno-Biology: The Immune System in Health and Science, 6th Edition; Janeway, Travers; 2005; Garland Science Publishing, New York; ISBN 0-8153-4101-6
- Immunology Introductory Textbook (ebook;revised 2nd edition); Nandini Shetty; New Age International (P) Limited, Publishers, India; 2005; ISBN 81-224-2335-3
- Instant Notes in Immunology, 2nd ed.; Lydyard, Whelan, Fanger; Taylor and Francis Group; 2004; China Version ISBN 703-025225-8； 46RMB Wangfujing Bookstore
- Medical Immunology—6th ed.; G. Virella, Editor; Informa Healthcare USA, Inc; 2007; ISBN 0-8493-9696-0
- Stem Cell Biology; Marshak, Gardner, Gottlieb; Cold Spring Harbor Laboratory Press; 2001; ISBN 0-87969-575-7/01
- Textbook of Human Development and Histology; Zhong Cuiping et al; Shanghai Scientific and Technical Publishers; 2006; ISBN 7-5323-8230-3
- Textbook of Medical Immunology (Immunology, 7th Edition); LIM Pak Leong; Elsevier (Singapore) Pte Ltd.; 2006; ISBN 0-323-03397-7