Although association between CMV infection and allograft rejection is well admitted, the precise mechanisms involved remain unclear. Characterization of alloreactive T cells in CMV positive kidney transplant patients allowed us to identify a monoclonal HLA-E-restricted CD8 alpha/beta T cell population displaying reactivity against peptides derived from the leader sequences of both HCMV-UL40 and allogeneic classical HLA-I molecules. Since HLA-E expression in vascularized organs is mainly restricted to endothelial cells (ECs), we investigated the reactivity of CMV-committed HLA-E-restricted T cells towards allogeneic ECs. We demonstrated that they efficiently recognized and killed in vitro allogeneic ECs isolated from a set of transplant donors. HLA-E-restricted CD8+T cell activation was TCR-dependent and occurs through crossrecognition of allogeneic HLA-class I peptides, independently of CMV infection. Moreover, we found that this alloreactivity is tightly regulated by NK receptors, especially by inhibitory KIR2DL2 that strongly prevents TCR-induced activation of this subset through recognition of HLA-C molecules. Therefore, while HLA-E-restricted T cells have the potential to control HCMV infection, they may also directly contribute to vascular lesions and graft rejection through recognition of peptides derived from allogeneic HLA-I molecules on graft ECs. Thus, we report here a new mechanism by which CMV infection may impair graft survival. Hence, a better evaluation of the role of HLA-E-restricted T cells in transplantation and of the impact of HLA-genotype, especially HLA-C, on their alloreactivity may determine whether they indeed represent a risk factor following organ transplantation.

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