Natural killer cell receptors regulate responses of HLA-E–restricted T cells
Lucy C. Sullivan, Thi H. O. Nguyen, Christopher M. Harpur, Sanda Stankovic, Abbie Kanagarajah, Marios Koutsakos, Philippa M. Saunders, Zhangying Cai, James A. Gray, Jacqueline Widjaja, Jie Lin, Gabriella Pietra, Maria Cristina Mingari, Lorenzo Moretta, Jerome Samir, Fabio Luciani, Glen Westall, Karl‐Johan Malmberg, Katherine Kedzierska, Andrëw G. Brööks
Abstract
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.