Long Sarah Alice, Muir Virginia S, Jones Britta E, Wall Valerie Z, Ylescupidez Alyssa, Hocking Anne M, Pribitzer Stephan, Thorpe Jerill, Fuchs Bryce, Wiedeman Alice E, Tatum Megan, Lambert Katharina, Uchtenhagen Hannes, Speake Cate, Ng Bernard, Heubeck Alexander T, Torgerson Troy R, Savage Adam K, Maldonado Michael A, Ray Neelanjana, Khaychuk Vadim, Liu Jinqi, Linsley Peter S, Buckner Jane H
Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Center for Systems Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.
Front Immunol. 2024 Apr 8;15:1383110. doi: 10.3389/fimmu.2024.1383110. eCollection 2024.
Exhausted CD8 T cells (T) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGITKLRG1 T with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGITKLRG1 T is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGITKLRG1 CD8 T population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive , together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells. In HC and RA subjects, lower levels of EOMES transcriptional modules and frequency of TIGITKLRG1 T were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and cytomegalovirus (CMV) seropositivity. Moreover, the frequency of TIGITKLRG1 T was significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig). The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of T may be more effective in DR4 subjects and T may be indirectly influenced by cellular interactions that are blocked by abatacept.
耗竭的CD8 T细胞（T细胞）在癌症中与较差的预后相关，但在自身免疫性疾病中却与较好的预后相关。基于我们过去在1型糖尿病（T1D）中使用替普珠单抗治疗后TIGIT⁺KLRG1⁺ T细胞增加的发现，在未进行治疗的情况下，我们发现TIGIT⁺KLRG1⁺ T细胞的频率在个体内是稳定的，但在T1D和健康对照（HC）队列中的个体之间存在差异。在HC、T1D、类风湿性关节炎（RA）和癌症患者中，这群TIGIT⁺KLRG1⁺ CD8 T细胞具有与耗竭相关的EOMES基因特征，表达多种抑制性受体，且反应低下，这共同表明TIGIT和KLRG1的共表达可能广泛定义了人类外周耗竭细胞。在HC和RA患者中，即使考虑疾病状态和巨细胞病毒（CMV）血清阳性情况，较低水平的EOMES转录模块和TIGIT⁺KLRG1⁺ T细胞频率也与RA HLA风险等位基因（DR0401、0404、0405、0408、1001）相关。此外，在接受阿巴西普（CTLA4Ig）治疗的RA HLA风险患者而非非风险患者中，TIGIT⁺KLRG1⁺ T细胞的频率显著增加。DR4关联以及阿巴西普的选择性调节表明，对T细胞的治疗性调节在DR4患者中可能更有效，并且T细胞可能受到被阿巴西普阻断的细胞间相互作用的间接影响。
