Acute allograft rejection is mediated by alloreactive CD8+ T cells that differentiate into cytotoxic lymphocytes (CTL). In most rodent models, CTL differentiate from naïve CD8+ T cells within secondary lymphoid organs in response to alloantigen presented by professional antigen presenting cells (APC). Human allografts may be rejected by circulating effector memory T (T_EM) cells that recognize non-self class I and II MHC molecules on graft endothelial cells (EC), infiltrate the graft and mediate rejection without involvement of professional APCs or secondary lymphoid organs. While much is known about the differentiation of rodent naïve CD8+ T cells into CTL, the requirements for differentiation of human CD8+ T_EM into CTL are not well defined. Here we tested if human CD4+ T_EM , activated by EC class II MHC molecules, are required for this process. Consistent with this hypothesis, preventing recognition of class II MHC molecules expressed by EC lining human artery segments that have been interposed into the aortae of immunodeficient mice reduces graft infiltration by adoptively transferred allogeneic human T cells as well as CD8+ T cell differentiation within and acute rejection of the human artery. In vitro, siRNA knockdown or CRISPR/Cas9 ablation of class II MHC molecules on allogeneic EC prevents CD4+ T_EM from producing sufficient IL-2 to help CD8+ T_EM to expand and differentiate into CTL in response to the same EC. Synthetic human microvessels formed by EC within collagen gels and then implanted into SCID/bg mice may be rejected by allogeneic T cells in a process that is mitigated by removal of CD8+ T cells. Microvessels engineered from human EC that had undergone CRISPR/Cas9-mediated ablation of class II MHC molecule expression are significantly protected from CD8+ T cell-mediated vessel destruction in vivo compared to control EC microvessels. We conclude that human CD8+ T_EM-mediated acute vascular rejection, which targets graft class I MHC molecules, requires help from CD4+ T_EM cells activated by recognition of class II MHC molecules on allogeneic EC. These preclinical studies predict that human allografts or tissue engineered constructs that incorporate allogeneic EC will be significantly less prone to CTL-mediated rejection.

CITATION INFORMATION: Abrahimi P, Qin L, Chang W, Bothwell A, Tellides G, Saltzman W, Pober J. Blocking MHC Class II on Human Endothelium Mitigates Acute Rejection of Vessel Allografts by Effector Memory T Cells. Am J Transplant. 2016;16 (suppl 3).

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