GRAFT-VERSUS-HOST-DISEASE-ASSOCIATED LYMPHOID HYPOPLASIA AND B-CELL DYSFUNCTION IS DEPENDENT UPON DONOR T-CELL-MEDIATED FAS-LIGAND FUNCTION, BUT NOT PERFORIN FUNCTION

Allogeneic bone marrow transplant recipients often exhibit a graft-ver sus-host-disease (GVHD)-associated immune deficiency that can be prolo nged and lead to life-threatening infections. We have examined the rol e of donor T cell-mediated cytotoxic function in the development of GV HD-associated immune deficiency, A major histocompatibility complex-ma tched model of allogeneic bone marrow transplantation was employed in which lethally irradiated C3H.SW mice received a nonlethal dose of T c ells from either perforin-deficient (B6-perforin 0/0), Fas-ligand (Fas L)-defective (B6-gld), or normal (B6) allogeneic donor mice, T cell-de pleted marrow from B6-Ly-5.1 congenic donor mice was transplanted alon g with the donor T cell populations to determine the effects of donor T cell-mediated cytotoxicity on engraftment. Our results demonstrate t hat recipients of perforin-deficient or normal allogeneic T cells exhi bit profound lymphoid hypoplasia and severely reduced splenic prolifer ative responses to lipopolysaccharide in vitro. In contrast, GVHD-asso ciated lymphoid hypoplasia is dramatically reduced and in vitro B cell function is intact in recipients of FasL-defective allogeneic T cells . Engraftment of myeloid and erythroid lineage cells occurs irrespecti ve of donor T cell cytotoxic function. Although recipients of perforin -deficient or normal allogeneic T cells exhibited hematopoietic engraf tment exclusively of donor origin, recipients of FasL-defective donor T cells exhibited significant mixed chimerism (Ly-5.1/Ly-5.2). Because only marrow of donor origin was transplanted, this finding suggests t hat Fas-mediated antirecipient cytotoxicity is required for clearance of residual hematopoietic stem cells of host origin that persist follo wing lethal irradiation.