Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, United States.
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, United States.
Front Immunol. 2023 Mar 7;14:997376. doi: 10.3389/fimmu.2023.997376. eCollection 2023.
At homeostasis, a substantial proportion of Foxp3 T regulatory cells (T) have an activated phenotype associated with enhanced TCR signals and these effector T cells (eT) co-express elevated levels of PD-1 and CTLA-4. Short term blockade of the PD-1 or CTLA-4 pathways results in increased eT populations, while combination blockade of both pathways had an additive effect. Mechanistically, combination blockade resulted in a reduction of suppressive phospho-SHP2 Y580 in eT cells which was associated with increased proliferation, enhanced production of IL-10, and reduced dendritic cell and macrophage expression of CD80 and MHC-II. Thus, at homeostasis, PD-1 and CTLA-4 function additively to regulate eT function and the ability to target these pathways in T cells may be useful to modulate inflammation.
在体内平衡状态下，相当一部分 Foxp3+ T 调节细胞（Treg）具有激活表型，与增强的 TCR 信号相关，这些效应 T 细胞（Teff）共同表达高水平的 PD-1 和 CTLA-4。短期阻断 PD-1 或 CTLA-4 通路会导致 Teff 群体增加，而同时阻断两条通路则具有相加效应。从机制上讲，联合阻断导致 Teff 细胞中抑制性磷酸化 SHP2 Y580 的减少，这与增殖增加、IL-10 产生增强以及树突状细胞和巨噬细胞 CD80 和 MHC-II 表达减少有关。因此，在体内平衡状态下，PD-1 和 CTLA-4 共同作用来调节 Teff 功能，靶向 T 细胞中这些通路的能力可能有助于调节炎症。
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