CD4 T cells mediate cardiac xenograft rejection via host MHC Class II

Abstract

Background Previous studies indicate that acute CD4 T-cell-mediated cardiac allograft rejection requires donor MHC class II expression and can be independent of ‘indirect’ antigen presentation. However, other studies suggest that indirect antigen presentation to CD4 T-cells may play a primary role in cellular xenograft immunity. Thus, the relative roles of direct/indirect CD4 T-cell reactivity against cardiac xenografts is unclear. We set out to determine the role for indirect CD4 T-cell reactivity in cardiac xenograft rejection. Methods Rat hearts were transplanted heterotopically into wild-type and immuno-deficient mice. Recipients were untreated, treated with depleting antibodies or reconstituted with wild-type cells. Results Antibody depletion confirmed that rat heart xenograft rejection in C57Bl/6 mice was CD4 T-cell-dependent. Also, heart xenografts survived long-term in B6 MHC class II (C2D) deficient mice. Graft acceptance in C2D mice was not secondary to CD4 T-cell deficiency alone, because transferred B6 CD4 T-cells failed to trigger rejection in C2D hosts. Furthermore, purified CD4 T-cells were sufficient for acute rejection of rat heart xenografts in immune-deficient B6rag1−/− recipients. Importantly, CD4 T-cells did not reject rat hearts in C2Drag1−/− hosts, contrasting results using cardiac allografts. ‘Direct’ xenoreactive CD4 T-cells were not sufficient to mediate rejection despite vigorous reactivity to rat stimulator cells in vitro. Conclusion Taken together, results show that CD4 T-cells are both necessary and sufficient for acute cardiac xenograft rejection and host MHC class II is critical in this process.

Immunosuppressive effect of arsenic trioxide on islet xenotransplantation prolongs xenograft survival in mice

“…It has been revealed that activated CD8 + T cells infiltrated cardiac allografts continuously within 72 h after transplantation, in which they promoted graft rejection via producing high levels of proinflammatory IFN-γ 25 , and the production of IFN-γ by CD8 + T cells has been speculated to be the rate-limiting step in process of allograft rejection 26 . And the CD4 + T cells has been demonstrated to be necessary and sufficient for cardiac allograft rejection, in which the intact host major histocompatibility complex (MHC) Class II is required 27 . Besides, the protective potential of CD4 + CD25 + Foxp3 + Treg cells has been identified in xenotransplantation 28 .…”

Deletion of Smad3 improves cardiac allograft rejection in mice

“…As immune regulatory cells, CD4 + T helper (Th) cells play a critical role in transplant rejection, especially in acute allograft rejection [ 1 ]. This is supported by the finding that adoptive transfer of CD4 + T cells promotes but depletion of this T cell population inhibits allograft rejection [ 2 , 3 ]. It is now clear that naive CD4 + T cells can proliferate and differentiate into Th cells including Th1, Th2, T regulatory (Treg) cells, and interleukin 17 (IL-17)-producing Th cells (Th17).…”

Blockade of Extracellular HMGB1 Suppresses Xenoreactive B Cell Responses and Delays Acute Vascular Xenogeneic Rejection

“…Since xenoreactive antibodies are essential for the pathogenesis of AVR , the inhibitory effect on xenoreactive B cell responses may represent one of the most important mechanisms by which HMGB1‐neutralizing antibody delays acute xenograft rejection. Since the generation of induced anti‐rat antibodies in our model is most likely a result of T cell–dependent B cell responses , the inhibition of xenoreactive B cell responses by blockade of extracellular HMGB1 may be correlated with the suppression of helper T cell activation. In our previous studies using a murine cardiac allotransplant model, blockade of extracellular HMGB1 was shown to be able to suppress the early Th1 and/or Th17 immune response .…”