One of the major characteristics of vertebrate immunology is thymic involution

Involution (medicine)

-Thymus:The thymus continues to grow between birth and puberty and then begins to atrophy, a process directed by the high levels of circulating sex hormones. Proportional to thymic size, thymic activity is most active before puberty. Upon atrophy, the size and activity are dramatically reduced,...

, the shrinking 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....

 with age, resulting in changes in the architecture of the thymus and a decrease in tissue mass. This process is a conserved sequence

Conserved sequence

In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...

 or (orthologous sequences) in almost all vertebrates, from birds, teleosts, amphibians to reptiles, though the thymi of a few species of sharks are known not to involute. T-cells are named for the thymus where T-lymphocyte

T cell

T 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...

s migrate from the bone marrow to mature. Its regression has been linked to the reduction in immunosurveillance in the elderly. Though thymic involution has been linked to senescence

Immunosenescence

Immunosenescence refers to the gradual deterioration of the immune system brought on by natural age advancement. It involves both the host’s capacity to respond to infections and the development of long-term immune memory, especially by vaccination...

, it is not induced by senescence as the organ starts involuting from a young age – as early as the first year of life in humans.

Prenatal Development

Though the thymus is fully developed before birth , newborns have an essentially empty peripheral immune compartment immediately after birth. Hence, T lymphocytes are not present in the peripheral lymphoid tissues

Lymphatic system

The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...

, where naïve, mature lymphocytes are stimulated to respond to pathogens. In order to populate the peripheral system, the thymus increases in size and upregulates its function during the early prenatal period .

Age-related Involution

Though some sources continue to cite puberty

Puberty

Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...

 as the time of onset, studies have shown thymic involution to start much earlier . The crucial distinction came from the observation that the thymus consists of two main components: the true thymic epithelial space (TES) and the perivascular space (PVS). Thymopoiesis, or T-cell maturation, only occurs in the former. In humans, the TES starts decreasing from the first year of life at a rate of 3% until middle age (35–45 years of age), whereupon it decreases at a rate of 1% until death. Hypothetically, the thymus should stop functioning at around 105 years of age ; but, studies with bone-transplant patients have shown that the thymi of the majority of patients over forty were unable to build a naïve T cell compartment.

Effects of the involution

The ability of the immune system to mount a strong protective response depends on the receptor diversity of naive T-cells

Naive T cell

A naive T cell or Th0 cell is a T cell that has differentiated in bone marrow, and successfully undergone the positive and negative processes of central selection in the thymus...

 (TCR). Thymic involution results in a decreased output of naïve T lymphocytes – mature T cells that are tolerant to self antigen

Antigen

An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

s, responsive to foreign antigens, but have not yet been stimulated by a foreign substance. In adults, naïve T-cells are hypothesized to be primarily maintained through homeostatic proliferation, or cell division of existing naïve T cells. Though homeostatic proliferation helps sustain TCR even with minimal to nearly absent thymic activity, it does not increase the receptor diversity. For yet unknown reasons, TCR diversity drops drastically around age 65. Loss of thymic function and TCR diversity is thought to contribute to weaker immunosurveillance

Cancer immunotherapy

Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease...

 of the elderly, including increasing instances of diseases such as cancers, autoimmunity, and opportunistic infections.

Acute thymic involution and treatment implications

There is growing evidence that thymic involution is plastic and can be therapeutically halted or reversed in order to help boost the immune system. In fact, under certain circumstances, the thymus has been shown to undergo acute thymic involution (alternatively called transient involution) . For example, transient involution has been induced in humans and other animals by stresses

Stress (biology)

Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...

  such as infection

Infection

An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

s , pregnancy

Pregnancy

Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...

 , and malnutrition

Malnutrition

Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....

 . The thymus has also been shown to decrease during hibernation

Hibernation

Hibernation is a state of inactivity and metabolic depression in animals, characterized by lower body temperature, slower breathing, and lower metabolic rate. Hibernating animals conserve food, especially during winter when food supplies are limited, tapping energy reserves, body fat, at a slow rate...

 and, in frogs, change in size depending on the season, growing smaller in the winter Studies on acute thymic involution may help in developing treatments

Immunotransplant

Immunotransplant is a maneuver used to make vaccines more powerful. It refers to the process of infusing vaccine-primed T lymphocytes into lymphodepleted recipients for the purpose of enhancing the proliferation and function of those T cells and increasing immune protection induced by that...

 for patients, who for example are unable to restore immune function after chemotherapy

Chemotherapy

Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

, ionizing radiation

Ionizing radiation

Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...

, or infections like HIV

HIV

Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

.

Evolutionary Mystery

Thymic involution remains an evolutionary mystery since it occurs in most vertebrates despite its negative effects. Since it is not induced by senescence, many scientists have hypothesized that there may have been evolutionary pressures for the organ to involute. A few hypotheses are as follows: Developing T cells that interact strongly with antigen being presented within the thymus are induced to undergo programmed cell death. The intended effect is deletion of self-reactive T cells. This works well when the antigen being presented within the thymus is truly of self origin, but antigen from pathogenic microbes that happens to infiltrate the thymus has the potential to subvert the entire process. Rather than deleting T cells that would cause autoimmunity, T cells capable of eliminating the infiltrating pathogen are deleted instead. It has been proposed that one way to minimize this problem is to produce as many long-lived T cells as possible during the time of life when the thymus is most likely to be pristine, which generally would be when organisms are very young and under the protection of a functional maternal immune system Thymus 24:29-40>. Thus, in mice and humans, for example, the best time to have a prodigiously functional thymus is prior to birth. In turn, it is well known from Williams' . theory of the evolution of senescence that strong selection for enhanced early function readily accommodates, through antagonistic pleiotropy, deleterious later occurring effects, thus potentially accounting for the especially early demise of the thymus. The disposable soma hypothesis and life history hypothesis say similarly that tradeoffs are involved in thymic involution. Since the immune system must compete with other bodily systems, notably reproduction, for limited physiological resources, the body must invest in the immune system differentially at different stages of life. There is high immunological investment in youth since immunological memory is low . There are also hypotheses that suggest that thymic involution is directly adaptive. For example, some hypotheses have proposed that thymic involution may help in avoidance of autoimmunity or other dangers , prevention of infection , and production of an optimal repertoire of T-cells. Zinc deficiency may also play a role

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