Journal article

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

Lucy C Sullivan, Thi HO Nguyen, Christopher M Harpur, Sanda Stankovic, Abbie R Kanagarajah, Marios Koutsakos, Philippa M Saunders, Zhangying Cai, James A Gray, Jacqueline ML Widjaja, Jie Lin, Gabriella Pietra, Maria Cristina Mingari, Lorenzo Moretta, Jerome Samir, Fabio Luciani, Glen P Westall, Karl J Malmberg, Katherine Kedzierska, Andrew G Brooks



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 inhibitor..

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Funding Acknowledgements

This work was funded by grants from the National Health and Medical Research Council (NHMRC) to A.G.B. and K.K. L.C.S. was supported by an NHMRC Career Development Award, and K.K. was supported by an NHMRC Senior Research Fellowship. We acknowledge the Melbourne Cytometry Platform (Doherty Institute node) for assistance with flow cytometry.