Sullivan Lucy C, Nguyen Thi H O, Harpur Christopher M, Stankovic Sanda, Kanagarajah Abbie R, Koutsakos Marios, Saunders Philippa M, Cai Zhangying, Gray James A, Widjaja Jacqueline M L, Lin Jie, Pietra Gabriella, Mingari Maria Cristina, Moretta Lorenzo, Samir Jerome, Luciani Fabio, Westall Glen P, Malmberg Karl J, Kedzierska Katherine, Brooks Andrew G
Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute, Parkville, Victoria 3010, Australia.
Lung Transplant Service, The Alfred Hospital and Monash University Melbourne, Victoria 3000, Australia.
Sci Immunol. 2021 Apr 23;6(58). 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.
人巨细胞病毒（CMV）感染可刺激强烈的人类白细胞抗原（HLA）-E限制性CD8 T细胞反应。这些T细胞识别来自UL40的一种肽，该肽与同样结合HLA-E的自身肽相比，差异小至一个甲基，这对它们避免自身反应性的能力提出了挑战。出乎意料的是，我们发现UL40/HLA-E T细胞受体（TCR）库中包含对HLA-E/自身肽具有高亲和力的TCR。然而，矛盾的是，对于对HLA-E具有高亲和力的TCR的UL40/HLA-E T细胞，观察到较低的细胞因子反应。RNA测序和流式细胞术分析表明，这些T细胞以抑制性自然杀伤细胞受体（NKR）KIR2DL1和KIR2DL2/L3的表达为特征。另一方面，携带低亲和力TCR的UL40/HLA-E T细胞表达激活受体NKG2C。携带高亲和力TCR的T细胞的激活受KIR2D受体与HLA-C之间相互作用的调节。这些发现确定了NKR信号在调节HLA-E限制性T细胞的自身/非自身识别中的作用，允许抗病毒反应同时避免同期的自身反应性。
