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

Sci Immunol. 2021 Apr 23;6(58):eabe9057. doi: 10.1126/sciimmunol.abe9057.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cytomegalovirus / immunology
  • Cytomegalovirus Infections / blood
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / virology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Natural Killer Cell / metabolism*
  • Viral Proteins / immunology
  • Viral Proteins / metabolism


  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • Receptors, Antigen, T-Cell
  • Receptors, Natural Killer Cell
  • UL40 glycoprotein, Cytomegalovirus
  • Viral Proteins