2023年12月12日，美国加州大学旧金山分校Arthur Weiss小组在《免疫》杂志发表论文。该研究表明，TCR信号促进具有pH敏感性磷酸酶活性的STS1-Cbl-b复合物的形成，从而抑制了T细胞在酸性环境中的功能。

研究人员发现T细胞受体（TCR）刺激诱导了E3-泛素连接酶Cbl-b与pH敏感的非常规磷酸酶STS1的分子复合物。诱导的相互作用取决于Cbl-b中的脯氨酸基团与STS1 SH3结构域的相互作用。STS1使与Cbl-b相互作用的磷酸化蛋白去磷酸化。在体外或体内，缺乏STS1或Cbl-b会以自分泌或旁分泌的方式降低T细胞反应对酸抑制作用的敏感性。

此外，STS1或Cbl-b的缺乏还能促进体内T细胞的增殖和分化活性，抑制肿瘤生长，延长存活时间，改善肿瘤模型中T细胞的适应性。因此，TCR诱导的STS1-Cbl-b复合物能感知细胞内或细胞外的酸度并调节T细胞反应，为提高抗肿瘤免疫力提供了潜在的治疗靶点。

据介绍，酸性环境会抑制T细胞反应。TCR诱导的蛋白质磷酸化受到去磷酸化和/或泛素化的负调控，但对酸性环境敏感的机制还不完全清楚。

附：英文原文

Title: TCR signaling promotes formation of an STS1-Cbl-b complex with pH-sensitive phosphatase activity that suppresses T cell function in acidic environments

Author: Yuan-Li Tsai, Marcel Arias-Badia, Theresa A. Kadlecek, Yee May Lwin, Aahir Srinath, Neel H. Shah, Zhi-En Wang, Diane Barber, John Kuriyan, Lawrence Fong, Arthur Weiss

Issue&Volume: 2023/12/12

Abstract: T cell responses are inhibited by acidic environments. T cell receptor (TCR)-inducedprotein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination,but the mechanisms underlying sensitivity to acidic environments are not fully understood.Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitinligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interactiondepended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acidin an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumormodels. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidityand regulates T cell responses, presenting a potential therapeutic target for improvinganti-tumor immunity.

DOI: 10.1016/j.immuni.2023.11.010

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00492-2