Thymic Involution - an Evolutionary Mystery
Review paper
An evolutionary perspective on the mechanisms of immunosenescence
There is an accumulating body of evidence that a decline in immune function with age is common to most if not all vertebrates. For instance, age- associated thymic involution seems to occur in all species that possess a thymus, indicating that this process is evolutionary ancient and conserved. The precise mechanisms regulating immunosenescence remain to be resolved, but much of what we do know is consistent with modern evolutionary theory. In this review, we assess our current knowledge from an evolutionary perspective on the occurrence of immunosenescence, we show that life history trade-offs play a key role and we highlight the possible advantages of the age-related decline in thymic function.
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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.[20] 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’[21] 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.[1] 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,[22] prevention of infection,[9] and production of an optimal repertoire of T-cells.[23] Zinc deficiency may also play a role[24].
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A thymus candidate in lampreys
Immunologists and evolutionary biologists have been debating the nature of the immune system of jawless vertebrates–lampreys and hagfish–since the nineteenth century. In the past 50 years, these fish were shown to have antibody-like responses and the capacity to reject allografts but were found to lack the immunoglobulin-based adaptive immune system of jawed vertebrates. Recent work has shown that lampreys have lymphocytes that instead express somatically diversified antigen receptors that contain leucine-rich-repeats, termed variable lymphocyte receptors (VLRs), and that the type of VLR expressed is specific to the lymphocyte lineage: T-like lymphocytes express type A VLR (VLRA) genes, and B-like lymphocytes express VLRB genes. These clonally diverse anticipatory antigen receptors are assembled from incomplete genomic fragments by gene conversion, which is thought to be initiated by either of two genes encoding cytosine deaminase, cytosine deaminase 1 (CDA1) in T-like cells and CDA2 in B-like cells. It is unknown whether jawless fish, like jawed vertebrates, have dedicated primary lymphoid organs, such as the thymus, where the development and selection of lymphocytes takes place. Here we identify discrete thymus-like lympho-epithelial structures, termed thymoids, in the tips of the gill filaments and the neighbouring secondary lamellae (both within the gill basket) of lamprey larvae. Only in the thymoids was expression of the orthologue of the gene encoding forkhead box N1 (FOXN1), a marker of the thymopoietic microenvironment in jawed vertebrates, accompanied by expression of CDA1 and VLRA. This expression pattern was unaffected by immunization of lampreys or by stimulation with a T-cell mitogen. Non-functional VLRA gene assemblies were found frequently in the thymoids but not elsewhere, further implicating the thymoid as the site of development of T-like cells in lampreys. These findings suggest that the similarities underlying the dual nature of the adaptive immune systems in the two sister groups of vertebrates extend to primary lymphoid organs.
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Thymus involution and regeneration: two sides of the same coin?
In vertebrates, the thymus is the main site of T cell development. The thymus reaches its maximum output during adolescence, after which it shrinks and generates fewer and fewer T cells. Physiological age-related involution of the thymus and failure to recover after injury are associated with impaired cellular immunity; hence, there is considerable interest in developing strategies to combat these deficiencies. In this Opinion article, we briefly review the phylogenetic and ontogenetic hallmarks of thymus development and function, and we discuss experimental models of impaired thymopoiesis and the molecular mechanisms of thymopoietic recovery. At each stage of the discussion we highlight the major gaps in our current knowledge.
