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

作者：Grazia Todd J^*; Plenter Robert J; Weber Sarah M; Lepper Helen M; Victorino Francisco; Zamora Martin R; Pietra Biagio A; Gill Ronald G

来源：Transplantation, 2010, 89(1): 33-39.

DOI：10.1097/TP.0b013e3181be6bc7

• Cytotoxicity
• Cytotoxic CD4 T cells
• Transplantation
• Acute rejection

Background. 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 perform (PFP) and/or Fast, (CD95L) were necessary for CD4 T cell-mediated rejection in vivo.
Methods. Wild-type C3H(H-2(k)) or Fas (CD95)-deficient C3Hlpr (H-2(k)) hearts were transplanted into immune-deficient C57B6rag(-/-) (H-2(b)) mice. Then, recipients were reconstituted with 11,naive purified CD4 T cells from wildtype, PFP-deficient, or Fast, (gld)-deficient T-cell donors.
Results. 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 CIA T-cell PFP completely abrogated acute rejection, despite the persistence of CD4 T cells within the graft.
Conclusions. 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.

• 出版日期2010-1-15