Costimulatory blockade induces hyporesponsiveness in T cells that recognize alloantigen via indirect antigen presentation

Background. Blockade of T cell costimulation by treatment with donor-specific transfusion (DST) and anti-CD 154 monoclonal antibody (mAb) induces prolonged allograft survival in mice. This effect is due in part to deletion of host CD8(+) and CD4(+) T cells that recognize alloantigen by direct presentation. The fate of host CD4(+) T cells that recognize alloantigen by indirect presentation, however, is unclear. Methods. We studied Tg361 TCR transgenic CD4(+) T cells that recognize alloantigen by indirect presentation. Carboxyfluorescein diacetate, succinimidyl ester-labeled Tg361 cells were adoptively transferred into syngeneic nontransgenic recipients and their fate in the peripheral blood, spleen, and lymph nodes following treatment with DST and anti-CD154 was analyzed. Results. Treatment of mice with DST plus anti-CD 154 mAb does not delete Tg361 CD4(+) T cells, but instead renders them hyporesponsive to rechallenge with alloantigen. Mice circulating hyporesponsive CD4(+) T cells also fail to reject skin allografts. The hyporesponsive state of the T cells is not reversed by the addition of interleukin-2, anti-CD28 mAb, or an agonistic anti-CD134 mAb in the presence of antigen. These T cells are capable of activation, however, as evidenced by in vitro proliferation in response to anti-CD3 mAb. Conclusions. These results demonstrate that costimulation blockade can induce hyporesponsiveness of host CD4(+) T cells recognizing alloantigens by indirect presentation, thus prolonging graft survival by a mechanism that does not involve deletion of alloreactive T cells.