Graft-versus-host disease (GVHD) is the most serious and common long-term complication of allogeneic hematopoietic cell transplantation, and is mediated by recognition of recipient minor or major histocompatibility antigens by donor T cells. Male recipients of hematopoietic cell grafts from MHC-matched female donors (F->M HCT) provide a unique opportunity to study the contribution of specific donor T cell responses to the development and persistence of graft-versus-host disease (GVHD). F-M HCT is characterized clinically by a higher incidence of both acute and historically defined chronic GVHD, as well as a longer mean duration of treatment for GVHD, than that seen in any other donor-recipient sex combination. At the cellular level, F-M transplants are characterized by the occurrence of donor (female) T cell responses against protein products of the Y chromosome - termed H-Yantigens - which are not possible in other donor-recipient combinations. Thus, the excess GVHD burden borne by F-MHCT recipients may in part be attributable to female T cell responses against H-Y antigens. The studies in this project will test the hypothesis that donor T cell responses against H-Y antigens contribute to GVHD among day +100 survivors after F-MHCT, and that long-term graft-host tolerance after F-MHCT will be associated with deletion, inactivation, or suppression of these responses. The results of these studies should provide insight into the mechanisms responsible for the development and persistence of GVHD, and will thereby provide the rationale and direction for future interventions aimed at overcoming alloreactivity and facilitating donor-host tolerance. The specific aims of this project are: (1) To define the specificity of the CD8+ and CD4+ effector T cell response to H-Y antigens in male recipients of hematopoietic cell grafts from MHC-matched female donors. (2) To determine whether the presence of H-Y-specific effector T cells in recipients of F-M HCT correlates with the presence of GVHD beyond day +100 after allogeneic HCT. (3) To determine whether the development of graft-host tolerance after F-MHCTis associated with deletion, inactivation, or suppression of H-Y-specific T cells. RELEVANCE (See instructions): The effectiveness of allogeneic hematopoietic cell transplantation for the treatment of blood diseases is significantly limited by a complication called graft-versus-host disease (GVHD). The studies described in this Project will investigate whether donor immune responses specifically recognizing the recipient are associated with the development of GVHD. These studies could potentially lead to improved strategies for preventing or treating GVHD in the future.