Abstract
Allograft rejection constitutes a major complication of solid organ transplantation requiring prophylactic/therapeutic immunosuppression, which increases susceptibility of patients to infections and cancer. Beyond the pivotal role of alloantigen-specific T cells and antibodies in the pathogenesis of rejection, natural killer (NK) cells may display alloreactive potential in case of mismatch between recipient inhibitory killer-cell immunoglobulin-like receptors (KIRs) and graft HLA class I molecules. Several studies have addressed the impact of this variable in kidney transplant with conflicting conclusions; yet, increasing evidence supports that alloantibody-mediated NK cell activation via FcγRIIIA (CD16) contributes to rejection. On the other hand, human cytomegalovirus (HCMV) infection constitutes a risk factor directly associated with the rate of graft loss and reduced host survival. The levels of HCMV-specific CD8+ T cells have been reported to predict the risk of posttransplant infection, and KIR-B haplotypes containing activating KIR genes have been related with protection. HCMV infection promotes to a variable extent an adaptive differentiation and expansion of a subset of mature NK cells, which display the CD94/NKG2C-activating receptor. Evidence supporting that adaptive NKG2C+ NK cells may contribute to control the viral infection in kidney transplant recipients has been recently obtained. The dual role of NK cells in the interrelation of HCMV infection with rejection deserves attention. Further phenotypic, functional, and genetic analyses of NK cells may provide additional insights on the pathogenesis of solid organ transplant complications, leading to the development of biomarkers with potential clinical value.
Highlights
Kidney transplantation is a widely used therapeutic intervention for chronic renal failure
CD94/NKG2A prevents the response against cells with a normal expression of HLA class I (HLA-I) molecules, complementing the function of killer-cell immunoglobulinlike receptors (KIRs)
In 2004, we discovered that healthy human cytomegalovirus (HCMV)-seropositive (HCMV+) individuals display increased proportions of natural killer (NK) and T cells hallmarked by high surface levels of CD94/NKG2C (NKG2Cbright) [56]
Summary
Kidney transplantation is a widely used therapeutic intervention for chronic renal failure. Inhibitory killer-cell immunoglobulinlike receptors (KIRs) and CD94/NKG2A complement each other, scanning potential target cells for altered surface expression of HLA class I (HLA-I) molecules. In the context of transplantation, NK cell subsets may react against normal allogeneic cells lacking specific HLA-I ligands for their inhibitory KIR (iKIR). In an example of convergent evolution, the physiological role of KIR is undertaken in mice by members of the Ly49 lectin-like family; the Ly49H receptor triggers NK cell functions upon interaction with the m157 viral protein, contributing to defense against murine CMV [9,10,11]. CD94/NKG2A prevents the response against cells with a normal expression of HLA-I molecules, complementing the function of KIRs. HLA-E may present pathogen-derived peptides [e.g., human cytomegalovirus (HCMV), HIV-1, and HCV] altering CD94/NKG2A recognition [18,19,20]. CD94/ NKG2C binds to HLA-E with lower affinity than its inhibitory counterpart [21, 22] and has been reported to be involved in the response to human HCMV (see Adaptive NK Cell Response to HCMV)
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