Allogeneic stem cell transplantation (SCT) remains an important therapeutic modality for a wide variety of malignant disease and is curative for many individuals who may not otherwise survive following treatment with chemotherapy alone. Infection remains a major cause of morbidity and mortality after SCT, and is largely attributable to impaired T cell immune reconstitution. To develop approaches to actively intervene to improve T cell reconstitution, it is crucial for us to systematically identify the factors governing T cell homeostasis after SCT. We hypothesize that the recipient thymus contributes to the recovery of naive and functional antigen-specific T cells after SCT, and that impaired thymic function results in delays in the recovery of these T cell subsets. We further hypothesize that the transfer of memory T cells in the donor graft may lead to more rapid T cell recovery after SCT, but that the transfer of activated memory T cells may facilitate the development of graft-versus-host disease in recipients. We hypothesize that GVHD impairs thymopoiesis in recipients and decreases the production of cytokines important in T cell homeostasis, and that immunosuppressive therapy for GVHD suppresses thymopoiesis and induces anergy in virus-specific memory CD8+ T cells. These hypotheses will be tested in the following Specific Aims: 1. To determine the role of the recipient thymus in the recovery of a diverse and functional T cell repertoire after stem cell transplantation. 2. To define how the transfer of memory T cells in the donor graft influences antigen-specific T cell recovery and GVHD in SCT recipients. 3. To determine whether GVHD and its treatment impair thymopoiesis and the function of antigen-specific memory T cells in SCT recipients.
