Gustafson Claire E, Qi Qian, Hutter-Saunders Jessica, Gupta Sheena, Jadhav Rohit, Newell Evan, Maecker Holden, Weyand Cornelia M, Goronzy Jörg J
Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, United States.
Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA, United States.
Front Immunol. 2017 Jun 14;8:692. doi: 10.3389/fimmu.2017.00692. eCollection 2017.
Aging is associated with an increased susceptibility to infection and a failure to control latent viruses thought to be driven, at least in part, by alterations in CD8 T cell function. The aging T cell repertoire is characterized by an accumulation of effector CD8 T cells, many of which express the negative regulatory receptor CD85j. To define the biological significance of CD85j expression on CD8 T cells and to address the question whether presence of CD85j in older individuals is beneficial or detrimental for immune function, we examined the specific attributes of CD8 T cells expressing CD85j as well as the functional role of CD85j in antigen-specific CD8 T cell responses during immune aging. Here, we show that CD85j is mainly expressed by terminally differentiated effector (TEMRAs) CD8 T cells, which increase with age, in cytomegalovirus (CMV) infection and in males. CD85j CMV-specific cells demonstrate clonal expansion. However, TCR diversity is similar between CD85j and CD85j compartments, suggesting that CD85j does not directly impact the repertoire of antigen-specific cells. Further phenotypic and functional analyses revealed that CD85j identifies a specific subset of CMV-responsive CD8 T cells that coexpress a marker of senescence (CD57) but retain polyfunctional cytokine production and expression of cytotoxic mediators. Blocking CD85j binding enhanced proliferation of CMV-specific CD8 T cells upon antigen stimulation but did not alter polyfunctional cytokine production. Taken together, these data demonstrate that CD85j characterizes a population of "senescent," but not exhausted antigen-specific effector CD8 T cells and indicates that CD85j is an important checkpoint regulator controlling expansion of virus-specific T cells during aging. Inhibition of CD85j activity may be a mechanism to promote stronger CD8 T cell effector responses during immune aging.
衰老与感染易感性增加以及无法控制潜伏病毒有关，这至少部分是由CD8 T细胞功能改变所致。衰老的T细胞库的特征是效应性CD8 T细胞积累，其中许多表达负调节受体CD85j。为了确定CD85j在CD8 T细胞上表达的生物学意义，并解决老年人中CD85j的存在对免疫功能是有益还是有害的问题，我们研究了表达CD85j的CD8 T细胞的具体特性以及CD85j在免疫衰老过程中抗原特异性CD8 T细胞反应中的功能作用。在此，我们表明CD85j主要由终末分化的效应性（TEMRA）CD8 T细胞表达，这些细胞在巨细胞病毒（CMV）感染和男性中随年龄增长而增加。CD85j CMV特异性细胞表现出克隆性扩增。然而，CD85j和CD85j细胞区室之间的TCR多样性相似，这表明CD85j不会直接影响抗原特异性细胞的库。进一步的表型和功能分析表明，CD85j识别出CMV反应性CD8 T细胞的一个特定亚群，这些细胞共表达衰老标志物（CD57），但保留多功能细胞因子产生和细胞毒性介质的表达。阻断CD85j结合可增强抗原刺激后CMV特异性CD8 T细胞的增殖，但不会改变多功能细胞因子的产生。综上所述，这些数据表明CD85j表征了一群“衰老”但未耗竭的抗原特异性效应性CD8 T细胞，并表明CD85j是控制衰老过程中病毒特异性T细胞扩增的重要检查点调节因子。抑制CD85j活性可能是在免疫衰老过程中促进更强CD8 T细胞效应反应的一种机制。
