Persisting alloantigen prevents primed CD45RC- CD4 T cells from inducing allograft rejection: implications for immunological memory.

Antigen stimulation induces specific CD4 T cells to change from a resting phenotype (CD45RC+) to a "memory" phenotype (CD45RC-), an isoform switch that is reversible and regulated by persisting antigen. We show here that CD4 T cells responsible for mediating allograft rejection undergo a similar CD45RC+ to CD45RC- switch irrespective of whether antigen priming results in sensitization or tolerance in vivo. Thus, skin allograft priming, designed to induce second set rejection, and a donor-specific blood transfusion (DST), designed to prolong cardiac allograft survival, will generate CD45RC- CD4 T cells that induce acute rejection when adoptively transferred to T cell-deficient athymic nude recipients. The ability of CD45RC- T cells, obtained from DST donors, to induce graft rejection was prevented by giving nude recipients a DST 14, 28 or even 56 days before grafting and T cell transfer. Thus, prolonged allograft survival in rats after DST was found to be strongly linked with persisting alloantigen from the blood transfusion but was not associated with detectable microchimerism. Importantly, CD45RC- T cells from skin graft-primed animals were similarly prevented from inducing rejection by residual DST-derived alloantigen. The investigation shows (1) that an allogeneic blood transfusion primes (not tolerizes) alloreactive CD4 T cells and (2) that residual DST-derived alloantigen can block the action of specifically primed "memory" CD4 T cells. These findings have implications for understanding immunological memory.