Research ArticleT CELLS

Natural killer cell receptors regulate responses of HLA-E–restricted T cells

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Science Immunology  23 Apr 2021:
Vol. 6, Issue 58, eabe9057
DOI: 10.1126/sciimmunol.abe9057

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NK receptors fine-tune T cells

The danger of autoreactivity lurks when CD8+ T cells specific for a viral peptide–MHC-I complex also have high affinity for a structurally similar self-peptide. Sullivan et al. assessed the self-peptide reactivity of human cytomegalovirus (CMV)–reactive T cells recognizing a viral UL40 peptide bound to HLA-E from 12 healthy CMV seropositive donors. T cells expressing TCRs with the highest affinity for self-peptide/HLA-E displayed the weakest functional responses. This paradoxical response correlated with increased expression of inhibitory NK receptors in the KIR family and decreased expression of the activating NKG2C receptor. These findings identify a mechanism involving calibrated display of NK receptors that enables HLA-E–restricted T cells to preserve their role as antiviral sentinels while avoiding the deleterious consequences associated with excess autoreactivity.

Abstract

Human cytomegalovirus (CMV) infection can stimulate robust human leukocyte antigen (HLA)–E–restricted CD8+ T cell responses. These T cells recognize a peptide from UL40, which differs by as little as a single methyl group from self-peptides that also bind HLA-E, challenging their capacity to avoid self-reactivity. Unexpectedly, we showed that the UL40/HLA-E T cell receptor (TCR) repertoire included TCRs that had high affinities for HLA-E/self-peptide. However, paradoxically, lower cytokine responses were observed from UL40/HLA-E T cells bearing TCRs with high affinity for HLA-E. RNA sequencing and flow cytometric analysis revealed that these T cells were marked by the expression of inhibitory natural killer cell receptors (NKRs) KIR2DL1 and KIR2DL2/L3. On the other hand, UL40/HLA-E T cells bearing lower-affinity TCRs expressed the activating receptor NKG2C. Activation of T cells bearing higher-affinity TCRs was regulated by the interaction between KIR2D receptors and HLA-C. These findings identify a role for NKR signaling in regulating self/non-self discrimination by HLA-E–restricted T cells, allowing for antiviral responses while avoiding contemporaneous self-reactivity.

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