CD4 T cells are both necessary and sufficient to mediate acute cardiac allograft rejection in mice. This process requires “direct” engagement of donor MHC class II molecules. That is, acute rejection by CD4+ T cells requires target MHC class II expression by the donor and not by the host. However, it is unclear whether CD4+ T cell rejection requires MHC class II expression on donor hemopoietic cells, nonhemopoietic cells, or both. To address this issue, bone marrow transplantation in mice was used to generate chimeric heart donors in which MHC class II was expressed either on somatic or on hemopoietic cells. We report that direct recognition of hemopoietic and nonhemopoietic cells are individually rate limiting for CD4+ T cell-mediated rejection in vivo. Importantly, active immunization with MHC class II+ APCs triggered acute rejection of hearts expressing MHC class II only on the somatic compartment. Thus, donor somatic cells, including endothelial cells, are not sufficient to initiate acute rejection; but they are necessary as targets of direct alloreactive CD4 T cells. Taken together, results support a two-stage model in which donor passenger leukocytes are required to activate the CD4 response while direct interaction with the somatic compartment is necessary for the efferent phase of acute graft rejection.
Natural killer cells are key components of the innate immune system. In
murine cardiac transplant models, donor-specific antibodies in concert with NK
cells are sufficient to inflict chronic allograft vasculopathy independently of
T and B cells. In this study, we aimed to determine the effector mechanism(s)
required by NK cells to trigger chronic allograft vasculopathy during
antibody-mediated rejection. Specifically, we tested the relative contribution
of the pro-inflammatory cytokine IFN-γ versus the contact-dependent
cytotoxic mediators of perforin and the CD95/CD95L (Fas/FasL) pathway for
triggering these lesions. C3H/HeJ cardiac allografts were transplanted into
immune-deficient C57BL/6 rag−/−γc−/−
recipients who also received monoclonal anti-MHC class I DSA. The combination of
donor-specific antibodies and wild-type NK cell transfer triggered aggressive
chronic allograft vasculopathy. However, transfer of IFN-γ-deficient NK
cells or host IFN-γ neutralization led to amelioration of these lesions.
Use of either perforin-deficient NK cells or CD95 (Fas)-deficient donors alone
did not alter development of vasculopathy, but simultaneous disruption of NK
cell-derived perforin and allograft Fas expression resulted in prevention of
these abnormalities. Therefore, both NK cell IFN-γ production and
contact-dependent cytotoxic activity are rate-limiting effector pathways that
contribute to antibody-induced chronic allograft vasculopathy.
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