Acute Cardiac Allograft Rejection by Directly Cytotoxic CD4 T Cells: Parallel Requirements for Fas and Perforin

• DOI: 10.1097/tp.0b013e3181be6bc7
• Publication Date: 2009-12-29T08:16:56Z
• Authors: Todd J. Grazia; Robert J. Plenter; Sarah M. Weber; Helen M. Lepper; Francisco Victorino; Martin R. Zamora; Biagio A. Pietra; Ronald G. Gill
• Keywords: CD4-Positive T-Lymphocytes; Graft Rejection; 0301 basic medicine; Mice, Inbred BALB C; Mice, Inbred C3H; Cell Survival; H-2 Antigens; Adoptive Transfer; Mice; 03 medical and health sciences; Acute Disease; CD4 Antigens; Animals; Heart Transplantation; Transplantation, Homologous; T-Lymphocytes, Cytotoxic

CD4 T cells can suffice as effector cells to mediate primary acute cardiac allograft rejection. Although CD4 T cells can readily kill appropriate target cells in vitro, the corresponding role of such cytolytic activity for mediating allograft rejection in vivo is unknown. Therefore, we determined whether the cytolytic effector molecules perforin (PFP) and/or FasL (CD95L) were necessary for CD4 T cell-mediated rejection in vivo.Wild-type C3H(H-2) or Fas (CD95)-deficient C3Hlpr (H-2) hearts were transplanted into immune-deficient C57B6rag (H-2) mice. Then, recipients were reconstituted with naïve purified CD4 T cells from wild-type, PFP-deficient, or FasL (gld)-deficient T-cell donors.In vitro, alloreactive CD4 T cells were competent to lyse donor major histocompatibility complex class II+ target cells, largely by a Fas-dependent mechanism. In vivo, the individual disruption of donor Fas expression (lpr) or CD4 T-cell-derived PFP had no significant impact on acute rejection. However, FasL-deficient (gld) CD4 T cells demonstrated delayed allograft rejection. Importantly, the simultaneous removal of both donor Fas expression and CD4 T-cell PFP completely abrogated acute rejection, despite the persistence of CD4 T cells within the graft.Results demonstrate that the direct rejection of cardiac allografts by CD4 effector T cells requires the alternative contribution of graft Fas expression and T cell PFP expression. To our knowledge, this is the first demonstration that cytolytic activity by CD4 T cells can play an obligate role for primary acute allograft rejection in vivo.