Mercadante Emily R, Lorenz Ulrike M
Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908.
J Immunol. 2017 Jul 1;199(1):129-137. doi: 10.4049/jimmunol.1602171. Epub 2017 May 26.
The balance between activation of T cells and their suppression by regulatory T cells (Tregs) is dysregulated in autoimmune diseases and cancer. Autoimmune diseases feature T cells that are resistant to suppression by Tregs, whereas in cancer, T cells are unable to mount antitumor responses due to the Treg-enriched suppressive microenvironment. In this study, we observed that loss of the tyrosine phosphatase SHP-1, a negative regulator of TCR signaling, renders naive CD4 and CD8 T cells resistant to Treg-mediated suppression in a T cell-intrinsic manner. At the intracellular level, SHP-1 controlled the extent of Akt activation, which has been linked to the induction of T cell resistance to Treg suppression. Finally, under conditions of homeostatic expansion, SHP-1-deficient CD4 T cells resisted Treg suppression in vivo. Collectively, these data establish SHP-1 as a critical player in setting the threshold downstream of TCR signaling and identify a novel function of SHP-1 as a regulator of T cell susceptibility to Treg-mediated suppression in vitro and in vivo. Thus, SHP-1 could represent a potential novel immunotherapeutic target to modulate susceptibility of T cells to Treg suppression.
在自身免疫性疾病和癌症中，T细胞的激活与其被调节性T细胞（Tregs）抑制之间的平衡失调。自身免疫性疾病的特征是T细胞对Tregs的抑制具有抗性，而在癌症中，由于富含Tregs的抑制性微环境，T细胞无法产生抗肿瘤反应。在本研究中，我们观察到酪氨酸磷酸酶SHP-1（TCR信号的负调节因子）的缺失，使初始CD4和CD8 T细胞以T细胞内在方式对Treg介导的抑制产生抗性。在细胞内水平，SHP-1控制Akt激活的程度，而Akt激活与T细胞对Treg抑制的抗性诱导有关。最后，在稳态扩增条件下，缺乏SHP-1的CD4 T细胞在体内抵抗Treg抑制。总体而言，这些数据确立了SHP-1作为设定TCR信号下游阈值的关键因子，并鉴定出SHP-1在体外和体内作为T细胞对Treg介导抑制易感性调节因子的新功能。因此，SHP-1可能代表一种潜在的新型免疫治疗靶点，用于调节T细胞对Treg抑制的易感性。
