Background While the role of Killer Ig-like receptors (KIRs) as important receptors for antigen recognition and function of Natural killer (NK) cells has long been established, their expression on a subset of CD8+ T cells has only recently been described. In healthy donors KIR+CD8+ T cells make up for 1%-38% of all CD8+ T cells, whereas increased percentages were found in a variety of autoimmune and infectious diseases, generating hypotheses assigning them with an immunoregulatory role. As such they could have a huge impact on CD8+ T cell immunity against oncologic, autoimmune or infectious diseases and the respective treatments aiming at improving or blocking CD8+ T cell function.
Materials and Methods We comprehensively analyzed a cohort of 10 cytomegalovirus (CMV)+ healthy donors for KIR expression on CD8+ T cells and the respective phenotype, specificity and function of these cells using combinatorial coding of pMHC multimers, DNA barcoded pMHC multimer screenings, multi-parametric flow cytometry and functional assays, comparing CMV-specific HLA-A and -B restricted CD8+ T cell responses with HLA-C restricted CD8+KIR+ T cell responses. We further aim to compare these findings to cancer-specific CD8+ T cell responses in a cohort of 10 melanoma patients.
Results We have demonstrated that KIR receptors can bind certain subgroups of peptide-MHC molecules. It seems to particularly be the case among peptide HLA-C complexes. We observe that certain pHLA-C multimers can bind and stain T cells via the KIR receptor. This follows the observations that HLA-C restricted CD8+ T cell responses are enriched in PBMCs from cohorts of melanoma, NSCLC, MDS, RCC and bladder cancer patients. We are currently further evaluating the role of KIR-HLA-C interaction in cancer-specific T cell responses. We found that KIR+CD8+ T cells resemble a distinct CD8+ T cell population and binding of pHLA-C multimers could be prevented by prior blocking of KIR receptors with antibodies, confirming TCR independent, KIR-mediated multimer binding. Interestingly, not all pHLA-C complexes will bind KIR receptors, and hence HLA-C binding to KIR seemed to be partially dependent on the specificity of the bound peptide.
Conclusions Here we show that KIR+CD8+ T cells are a distinct cell population identified by TCR independent HLA-C-KIR interaction. Analyses of specificity, phenotype and functionality of this cell population, elevated in the context of autoimmune, infectious and oncologic diseases, will enable us to assess their role in CD8+ T cell immunity.
Disclosure Information J.S. Kemming: None. A. Kongsgaard: None. N.P. Kristensen: None. S.K. Saini: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Tetramer Shop. S.R. Hadrup: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Tetramer Shop, PokeACell, Immumap.
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