In transplantation, direct-pathway CD8 T cells that recognize alloantigen on donor cells require CD4 help for activation and cytolytic function. The ability of indirect-pathway CD4 T cells to provide this help remains unexplained, because a fundamental requirement for epitope linkage is seemingly broken. The simultaneous presentation, by host dendritic cells (DCs), of both intact MHC class I alloantigen and processed alloantigen would deliver linked help, but has not been demonstrated definitively.
Here, we report that following in vitro co-culture with BALB/c DCs, small numbers (~1.5%) of C57BL/6 DCs presented acquired H-2d alloantigen both as processed allopeptide and as unprocessed antigen. This re-presented class I alloantigen provides a conformational epitope for direct-pathway allorecognition, because C57BL/6 DCs isolated from co-cultures and transferred to naïve C57BL/6 mice provoked cytotoxic CD8 T cell alloimmunity. Crucially, this response was dependent upon simultaneous presentation of class II-restricted allopeptide, because despite acquiring similar amounts of H-2d alloantigen upon co-culture, MHC class II-deficient C57BL/6 DCs failed to elicit cytotoxic alloimmunity. The relevance of this pathway to solid organ transplantation was then confirmed by the demonstration that CD8 T cell cytotoxicity was provoked in secondary recipients by transfer of DCs purified from wild-type, but not from MHC class II-deficient, C57BL/6 recipients of BALB/c heart transplants.
These experiments demonstrate that re-presentation of conformationally-intact MHC alloantigen by recipient APC can induce cytotoxic alloimmunity, but simultaneous co-presentation of processed allopeptide is essential, presumably because this facilitates linked recognition by indirect-pathway helper CD4 T cells.
Fc gamma receptors (FcγR) provide important immunoregulation. Targeting inhibitory FcγRIIb may therefore prolong allograft survival, but its role in transplantation has not been addressed. FcγRIIb signaling was examined in murine models of acute or chronic cardiac allograft rejection by transplanting recipients that either lacked FcγRIIb expression (FcγRIIb−/− ) or over-expressed FcγRIIb on B cells (BTG). Acute heart allograft rejection occurred at the same tempo in FcγRIIb−/− C57Bl/6 (B6) recipients as WT recipients, with similar IgG alloantibody responses. In contrast, chronic rejection of MHC class II-mismatched bm12 cardiac allografts was accelerated in FcγRIIb−/− mice, with development of more severe transplant arteriopathy and markedly augmented effector autoantibody production. Autoantibody production was inhibited, and rejection delayed, in BTG recipients. Similarly, whereas MHC class I-mismatched B6.Kd hearts survived indefinitely and remained disease-free in B6 mice, much stronger alloantibody responses and progressive graft arteriopathy developed in FcγRIIb−/− recipients. Notably, FcγRIIb-mediated inhibition of B6.Kd heart graft rejection was abrogated by increasing T cell help through transfer of additional H2.Kd-specific CD4 T cells.
Thus, inhibitory FcγRIIb signaling regulates chronic but not acute rejection, most likely because the supra-optimal helper CD4 T cell response in acute rejection overcomes FcγRIIb-mediated inhibition of the effector B cell population. Immunomodulation of FcγRIIb in clinical transplantation may hold potential for inhibiting progression of transplant arteriopathy and prolonging heart transplant survival.
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