THYMIC-INDEPENDENT T-CELL REGENERATION OCCURS VIA ANTIGEN-DRIVEN EXPANSION OF PERIPHERAL T-CELLS RESULTING IN A REPERTOIRE THAT IS LIMITED IN DIVERSITY AND PRONE TO SKEWING

Thymic regenerative capacity in humans decreases with age, suggesting that thymic-independent pathways of T cell regeneration may predominat e during adulthood. Using a murine bone marrow transplantation model, we present evidence that thymic-independent T cell regeneration occurs primarily via expansion of peripheral T cells and is Ag driven since significant expansion of CD4(+) or CD8(+) transgenic (Tg(+))/TCR-beari ng cells occurs only in the presence of Ag specific for the TCR. Such expansion resulted in skewing of the regenerated repertoire with 40 to 65% of the regenerated CD4(+) or CD8(+) T cells expressing the Tg(+)/ TCR in thymectomized hosts after bone marrow transplantation. In exper iments in which nontransgenic populations are used as T cell inocula, we noted decreased CD4 expansion when Class II MHC was blocked by mAb treatment in vivo, and CD8 expansion failed to occur in Class I MHC-de ficient hosts providing evidence that T cell regeneration in thymic-de ficient hosts largely occurs via TCR-MHC-mediated selection of periphe ral T cell populations. This process results in a T cell repertoire co mprised exclusively of T cells recently activated by the antigenic mil ieu of the host, with negligible numbers of residual ''naive'' cells b earing TCRs for Ags absent at the time of expansion. These findings ha ve important implications for approaches to enhance T cell regeneratio n in humans and provide evidence that vaccine strategies could skew th e T cell repertoire toward a specific antigenic target if administered to thymic-deficient hosts during immune reconstitution.