We studied the effects of the indirect pathway of allograft recognition using T cells from TCR transgenic Marilyn mice, which recognize the male Ag HY in an IA b-restricted fashion. The T cells are not alloreactive to the H-2 k haplotype, because they are not activated when adoptively transferred into recombinase-activating gene-2−/− common γ-chain−/− double-mutant H-2 k male or female mice. However, skin from H-2 k males, but not from H-2 k females, is acutely rejected by recombinase-activating gene-2−/− transgenic female recipients. In vitro, Marylin spleen cells primed by H-2 k skin grafting proliferated and secreted both IL-4 and IFN-γ in response to H-2 k male stimulators. However, the removal of H-2 b APC from the responding population abolished the response. Taken together, these results show that the indirect recognition that triggers rejection in this model is due to the recognition of HY Ag shed from H-2 k male allograft and presented by the recipient’s own IA b APC to transgenic T cells. This study demonstrates unequivocally the capacity of naive CD4+ T cells to promote the rejection of allografts through mechanisms that involve indirect destruction of grafted tissues.