HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation

Abstract

Natural killer (NK) cells are innate lymphocytes that can kill diseased- or virally-infected cells, mediate antibody dependent cytotoxicity and produce type I immune-associated cytokines upon activation. NK cells also contribute to the allo-immune response upon kidney transplantation either by promoting allograft rejection through lysis of cells of the transplanted organ or by promoting alloreactive T cells. In addition, they protect against viral infections upon transplantation which may be especially relevant in patients receiving high dose immune suppression. NK cell activation is tightly regulated through the integrated balance of signaling via inhibitory- and activating receptors. HLA class I molecules are critical regulators of NK cell activation through the interaction with inhibitory- as well as activating NK cell receptors, hence, HLA molecules act as critical immune checkpoints for NK cells. In the current review, we evaluate how NK cell alloreactivity and anti-viral immunity are regulated by NK cell receptors belonging to the KIR family and interacting with classical HLA class I molecules, or by NKG2A/C and LILRB1/KIR2DL4 engaging non-classical HLA-E or -G. In addition, we provide an overview of the methods to determine genetic variation in these receptors and their HLA ligands.

Keywords: HLA class I; KIR; NK cell; NKG2A; solid organ transplantation.

Figure 1

Potential role for NK cells in promoting allograft rejection. NK cells can contribute to allograft rejection in several ways: (A) By mediating direct cytoxicity against cells of the allograft that increasingly express cellular-stress or virus-associated activating ligands. (B) Via antibody-dependent cellular cytoxicity upon binding of CD16 on the NK cell to anti-HLA antibodies. (C) By producing proinflammatory cytokines like IFN-ϒ, that promote Th1 polarization of CD4⁺ cells, priming and activation of CD8⁺ T cells directed against the allograft and by stimulating B cell production of pathogenic IgG antibodies. iNKR, inhibitory NK cell receptor; aNKR, activating NK cell receptor.

Figure 2

KIR haplotypes and the potential effects of KIR-HLA interaction. (A) Based on the KIR gene content two haplotypes can be distinguished. The A haplotype containing KIR2DS4 as the only activating receptor and the B haplotype containing multiple combinations of activating- and inhibitory KIR genes. Depending on the exact combination of KIR genes, multiple different B haplotypes are known (https://www.ebi.ac.uk/ipd/kir/sequenced_haplotypes.html). (B) Recipient NK cells may encounter their HLA class I ligands on the kidney allograft (KIR ligand match) or not (KIR ligand mismatch). Even in the presence of class I ligand, stress- or infection associated ligands for activating receptors, including activating KIR, on the allograft can trigger NK cell cytotoxicity (induced-self by aKIR). iKIR, inhibitory killer immunoglobulin-like receptor; aKIR, activating killer immunoglobulin-like receptor.

Figure 3

Explanation of nomenclature used for HLA (A) and KIR (B). Figure adapted from the IPD-IMGT/HLA and IPD-KIR database website, respectively (85, 86).

Figure 4

Illustration and comparison of different HLA typing methods and the generally obtained typing resolution level. The figure depicts HLA-C as an example. Depending on the number of sequence specific primers or probes the PCR-SSP/SSO method can have low or intermediate resolution typing result. A*24AGK: string of different A*24 alleles. A*24:02G: group of alleles with identical peptide binding groove, but differences outside (including null alleles). A*24:02P: group of proteins with identical peptide binding groove, but differences outside (excluding null alleles).