For several reasons, it is unlikely that the composition of the suppressor T cell pool as it exists in a normal immune system is a linear projection of the intrathymically generated pool. First, extrathymic conversion of conventional, naive CD4 T cells into suppressor T cells may modulate the composition of the peripheral suppressor T cell pool. Although this has at present only been demonstrated in certain experimental systems (see preceding section), it appears reasonable to assume that the normal immune system in the steady state exploits similar pathways. Furthermore, there is accumulating evidence that the repertoire of suppressor T cells undergoes dynamic changes that are dictated by competition for survival factors such as access to cognate antigen or "niches" in the immune system. Among polyconal (non-TCR-transgenic) model systems, the most straightforward evidence in favor of interplay between an intra- and extrathymic encounter of self-antigen in the shaping of the repertoire of suppressor T cells has been obtained in a model of autoimmune thyroiditis in neonatally thymectomized rats . In this model, transfer of peripheral or thymic CD4 T cells from normal, euthymic rats prevented the development of the disease. Strikingly, when the thyroid of the donor animals had been ablated with1311, only thymic, but not peripheral CD4 T cells prevented disease. The most reasonable interpretation is that thyroid-specific suppressor T cells are generated in the thymus, and that after exit into the periphery these cells require continuous access to the respective self-antigen(s) in order to maintain functional suppressive activity toward a particular organ . Unless the antigen-specific suppressor T cells can be directly visualized, it remains unclear whether this loss of suppressive potential indicates a physical loss of the respective suppressor T cells or persisting cells have lost their suppressive activity. Again, TCR transgenic models of antigen-specific suppressor T cells can be expected to be instrumental in clarifying this issue.
When Walker et al. compared the frequency of Ova-specific CD25+ suppressor T cells within several peripheral lymphoid organs in the RIP-mOva x DO11.10 model, they found that these cells were enriched in the pancreatic lymph node . This clearly documents that suppressor T cells are "aware" of their cognate antigen in the steady state in vivo, and it is tempting to speculate that organ-specific suppressor T cells, after their generation in the thymus, preferentially occupy antigen-exposed microenvironments, i.e., those lymph nodes that drain the respective organ. Thus, each draining lymph node may harbor a particular ensemble of suppressive specificities that reflects the local representation of self-antigen. Since at present this experimental system is quite unique, more experimental evidence is needed to verify this hypothesis, and to what extent this observation can be generalized remains open. Two, mutually nonexclusive, hypotheses may be put forward to explain the enrichment of specific suppressor T cells in antigen-exposed microenvironments. First, after their generation in the thymus, suppressor T cells may circulate through the body very much like conventional T cells. Upon specific antigen recognition it may be that they change their migration behavior, resulting in their specific retention and accumulation at antigen-exposed sites. Alternatively, peripheral antigen recognition may induce proliferation and expansion of specific suppressor T cells in situ, wherever cognate antigen is presented, likewise leading to an enrichment of particular antigen specificities in a permissive microenvironment. The latter scenario is in obvious contradiction to the concept of anergy of CD25+ suppressor T cells, yet, as will be discussed later, there is accumulating experimental evidence challenging the view that CD25+ suppressor T cells are truly anergic. As a consequence, specificities for antigens presented by APC in the thymus, but not in the periphery, may have a selective disadvantage and maybe gradually lost from the pool of suppressor T cells.
Taken together, it appears that post- or extrathymic encounter of self-antigen plays a critical and dynamic role in shaping the repertoire of suppressor T cells.
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