Donor IFN-γ Receptors Are Critical for Acute CD4+ T Cell-Mediated Cardiac Allograft Rejection

Abstract

Recent studies using mouse models demonstrate that CD4+ T cells are sufficient to mediate acute cardiac allograft rejection in the absence of CD8+ T cells and B cells. However, the mechanistic basis of CD4-mediated rejection is unclear. One potential mechanism of CD4-mediated rejection is via elaboration of proinflammatory cytokines such as IFN-γ. To determine whether IFN-γ is a critical cytokine in CD4-mediated acute cardiac allograft rejection, we studied whether the expression of IFN-γ receptors on the donor heart was required for CD4-mediated rejection. To investigate this possibility, purified CD4+ T cells were transferred into immune-deficient mice bearing heterotopic cardiac allografts from IFN-γ receptor-deficient (GRKO) donors. While CD4+ T cells triggered acute rejection of wild-type heart allografts, they failed to trigger rejection of GRKO heart allografts. The impairment in CD4-mediated rejection of GRKO hearts appeared to primarily involve the efferent phase of the immune response. This conclusion was based on the findings that GRKO stimulator cells provoked normal CD4 proliferation in vitro and that intentional in vivo challenge of CD4 cells with wild-type donor APC or the adoptive transfer of in vitro primed CD4 T cells failed to provoke acute rejection of GRKO allografts. In contrast, unseparated lymph node cells acutely rejected both GRKO and wild-type hearts with similar time courses, illustrating the existence of both IFN-γ-dependent and IFN-γ-independent mechanisms of acute allograft rejection.

Long-Term Cardiac Allograft Survival across an MHC Mismatch after “Pruning” of Alloreactive CD4 T Cells

“…There was a more significant reduction in the number of IFN-␥-positive cells by ELISPOT of ND splenocytes stimulated with donor as compared with third-party B10.BR, whereas the splenocytes from mice reconstituted with dividing cells showed both a stronger proliferative response and greater number of IFN-␥-producing cells in response to the stimulator strain than a third-party stimulus. This is in keeping with other groups where IFN-␥ is a requirement for CD4 ϩ T cell-mediated rejection (47). It also in keeping with tolerance studies where lower donor-induced IFN-␥ production rather than proliferation is associated with tolerance, suggesting that rejection is a function of the phenotype of the T cells as well as their proliferative ability (48).…”

Immunological Disruption of Antiangiogenic Signals by Recruited Allospecific T Cells Leads to Corneal Allograft Rejection

“…Because Rag 2/2 mice are deficient in mature T and B cells, immunological rejection of an allotransplant should not occur, and the kinetics of endostatin production and prevention of neovascularization should be similar to those seen in syngeneic transplants (34,35 (Fig. 3A).…”

Allograft Rejection in a New Allospecific CD4+ TCR Transgenic Mouse

“…In the context of transplantation, major questions still exist concerning the relative contributions and requirements for CD4 vs. CD8 cells in different types of organ and tissue rejection (1)(2)(3)(4)(5)(6). For transplantation responses, there is a unique situation of alloantigen recognition, with direct recognition of allo-MHC on donor antigen-presenting cells, and indirect recognition of peptides derived from allo-MHC molecules presented on self-MHC (7).…”

“…These systems provide extremely powerful tools to investigate the roles of defined cell populations in the pathogenesis of in vivo immune responses. Furthermore, they permit investigators to track individual T cells of known antigenic specificity, thus providing additional insight into the in vivo fate and function of individual antigen-reactive T cells (1)(2)(3)(4).…”