Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455.
J Immunol. 2013 Oct 1;191(7):3681-93. doi: 10.4049/jimmunol.1201954. Epub 2013 Aug 30.
A hallmark of T cell activation in vitro and in vivo is the clustering of T cells with each other via interaction of the LFA-1 integrin with ICAM-1. The functional significance of these homotypic aggregates in regulating T cell function remains unknown. We used an APC-free in vitro activation system to demonstrate that stimulation of purified naive CD8 T cells results in enhanced expression of ICAM-1 on T cells that is sustained by the inflammatory cytokine IL-12 and associated with robust T cell aggregates. ICAM-1-deficient CD8 T cells proliferate normally but demonstrate a striking failure to aggregate. Interestingly, loss of ICAM-1 expression results in elevated levels of IFN-γ and granzyme B, as well as enhanced cytotoxicity. Similar results were obtained when anti-LFA-1 Ab was used to block the clustering of wild-type T cells. ICAM-1 ligation is not required for IFN-γ regulation, as clustering of ICAM-1-deficient CD8 T cells with wild-type T cells reduces IFN-γ expression. Analysis using a fluorescent reporter that monitors TCR signal strength indicates that T cell clustering limits T cell exposure to Ag during activation. Furthermore, T cell clustering promotes the upregulation of the CTLA-4 inhibitory receptor and the downregulation of eomesodermin, which controls effector molecule expression. Activation of ICAM-1-deficient CD8 T cells in vivo results in an enhanced percentage of KLRG-1(+) T cells indicative of short-lived effectors. These results suggest that T cell clustering represents a mechanism that allows continued proliferation but regulates T cell effector function and differentiation.
T 细胞在体外和体内激活的一个标志是通过 LFA-1 整合素与 ICAM-1 的相互作用，彼此之间的 T 细胞聚集。这些同源聚集在调节 T 细胞功能中的功能意义尚不清楚。我们使用无 APC 的体外激活系统证明，刺激纯化的幼稚 CD8 T 细胞导致 T 细胞上 ICAM-1 的表达增强，这是由炎症细胞因子 IL-12 维持的，并与强大的 T 细胞聚集相关。ICAM-1 缺陷型 CD8 T 细胞正常增殖，但明显无法聚集。有趣的是，ICAM-1 表达的丧失导致 IFN-γ 和颗粒酶 B 的水平升高，以及增强的细胞毒性。当使用抗 LFA-1 Ab 阻断野生型 T 细胞的聚集时，也获得了类似的结果。ICAM-1 配体对于 IFN-γ 的调节不是必需的，因为与野生型 T 细胞聚集的 ICAM-1 缺陷型 CD8 T 细胞降低了 IFN-γ 的表达。使用监测 TCR 信号强度的荧光报告基因的分析表明，T 细胞聚集在激活过程中限制 T 细胞暴露于 Ag。此外，T 细胞聚集促进 CTLA-4 抑制性受体的上调和控制效应分子表达的 eomesodermin 的下调。体内激活 ICAM-1 缺陷型 CD8 T 细胞导致 KLRG-1(+)T 细胞的百分比增加，表明其为短命效应器。这些结果表明，T 细胞聚集代表了一种允许持续增殖但调节 T 细胞效应功能和分化的机制。
