Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD 21201.
Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14342-14353. doi: 10.1073/pnas.1922525117. Epub 2020 Jun 8.
Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5 T cells expressed more of the NF-κB p65 protein than CD5 cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB depot potentially confers a survival advantage to CD5 T cells over CD5 ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide-induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.
未成熟 T 细胞在胸腺中经历阳性选择过程，当它们的新 T 细胞受体 (TCR) 与自身肽结合并响应信号时。随着 T 细胞的成熟，一系列负调控分子，包括抑制性表面糖蛋白 CD5，会随着自身肽信号的强度上调。这些调节剂共同抑制 TCR 近端信号传递，并有助于避免自身肽随后对外周 T 细胞的激活。矛盾的是，最初表达更多 CD5（CD5）的抗原特异性 T 细胞已被发现在外周挑战后更能作为效应/记忆细胞持续存在。CD5 功能的这种双重性的分子机制尚不清楚。我们发现 CD5 改变了静止外周 T 细胞中 NF-κB 信号的基础活性。当条件性敲除 CD5 时，T 细胞无法维持更高的细胞质 NF-κB 抑制剂 IκBα的表达。与此一致，在没有 TCR 信号的情况下，静止的 CD5 T 细胞比 CD5 细胞表达更多的 NF-κB p65 蛋白，而转录本水平没有显著增加。这种翻译后稳定的细胞 NF-κB 储存库可能赋予 CD5 T 细胞相对于 CD5 T 细胞的生存优势。总之，这些数据表明了一个两步模型，即自身肽诱导的 TCR 信号的强度导致 CD5 的上调，随后在准备响应激动性抗原驱动的 T 细胞激活的外周 T 细胞中维持 NF-κB 的比例储备。
