Martinez Gustavo J, Pereira Renata M, Äijö Tarmo, Kim Edward Y, Marangoni Francesco, Pipkin Matthew E, Togher Susan, Heissmeyer Vigo, Zhang Yi Chen, Crotty Shane, Lamperti Edward D, Ansel K Mark, Mempel Thorsten R, Lähdesmäki Harri, Hogan Patrick G, Rao Anjana
Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; Department of Information and Computer Science, Aalto University School of Science, Aalto 00076, Finland.
Immunity. 2015 Feb 17;42(2):265-278. doi: 10.1016/j.immuni.2015.01.006. Epub 2015 Feb 10.
During persistent antigen stimulation, CD8(+) T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) T cells to protect against Listeria infection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) T cells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.
在持续的抗原刺激下，CD8(+) T细胞的效应功能逐渐下降，这被称为耗竭，它会损害在肿瘤和感染情况下的免疫反应。在此，我们证明转录因子NFAT控制T细胞耗竭程序。当在细胞中表达时，一种无法与AP-1转录因子相互作用的工程化形式的NFAT1会减弱T细胞受体（TCR）信号传导，增加抑制性细胞表面受体的表达，并干扰CD8(+) T细胞在体内抵御李斯特菌感染和减缓肿瘤生长的能力。我们确定了原代CD8(+) T细胞中内源性和工程化NFAT1所占据的基因组区域，并表明工程化NFAT1直接诱导的基因与体内耗竭的CD8(+) T细胞中表达的基因重叠。我们的数据表明，NFAT通过结合不需要与AP-1合作的位点来促进T细胞无反应性和耗竭。
