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

Lucy C SullivanThi H O NguyenChristopher M HarpurSanda StankovicAbbie R KanagarajahMarios KoutsakosPhilippa M SaundersZhangying CaiJames A GrayJacqueline M L WidjajaJie LinGabriella PietraMaria Cristina MingariLorenzo MorettaJerome SamirFabio LucianiGlen P WestallKarl-Johan MalmbergKatherine KedzierskaAndrew G Brooks
Published in: Science immunology (2022)
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.
Keyphrases
  • single cell
  • endothelial cells
  • signaling pathway
  • herpes simplex virus
  • poor prognosis
  • regulatory t cells
  • bone marrow
  • mass spectrometry
  • epstein barr virus
  • nk cells
  • pluripotent stem cells