免疫检查点受体包括一些抑制性受体，这些受体可以限制免疫反应期间的组织损伤。阻断PD-1/PD-L1检查点受体轴路已经引起了癌症免疫治疗的范式转变，但也会导致自身免疫不良反应，尤其是甲状腺自身免疫。虽然PD-L1已知会在自身免疫腺体的甲状腺滤泡细胞（TFCs）上表达，但PD-1/PD-L1在T细胞和甲状腺细胞之间的作用还没有研究。在这里，我们报告说原代TFCs可以抑制CD4和CD8 T细胞增殖，但不会抑制细胞因子产生。然而，这种效应并不是通过PD-1/PD-L1或局部产生的细胞因子介导的。β-半乳糖苷酶分析排除了培养诱导的衰老作为其解释。高分辨率流式细胞术表明，自体TFC/T细胞共培养诱导了数个双阴性（DN）T细胞群的扩张，这些T细胞群具有高表达活化标志和负的免疫检查点。单细胞转录组学分析表明，解离后的TFC表达了很多候选分子，可以介导这种抑制活性，包括CD40、E-Cadherin和TIGIT配体。这些配体直接或通过产生一个抑制性的DN T细胞群，而不是通过PD-1/PD-L1轴路，最有可能是TFC免疫抑制活性的责任。这些结果有助于揭示在组织水平上限制自身免疫的复杂抑制机制网络，但也指出了除了PD-1/PD-L1外，还可以贡献于肿瘤逃避的途径。版权所有 © 2023 Elsevier Ltd.。

Immune Checkpoint Receptors include a number of inhibitory receptors that limit tissue damage during immune responses; blocking PD-1/PD-L1 checkpoint receptor axis led to a paradigm shift in cancer immunotherapy but also to autoimmune adverse effects, prominently thyroid autoimmunity. Although PD-L1 is known to be expressed on thyroid follicular cells (TFCs) of autoimmune glands the role on PD-1/PD-L1 in the interaction between T cells and thyroid cells in the tissue has not been investigated. Here we report that autologous primary TFCs, but not transformed TFCs, inhibit CD4 and CD8 T cell proliferation but no cytokine production. This effect is not, however, mediated by PD-1/PD-L1 nor locally produced cytokines. Beta galactosidase analysis excluded culture-induced senescence as an explanation. High resolution flow cytometry demonstrated that autologous TFC/T cells co-culture induced the expansion of several clusters of double negative (DN) T cells characterized by high expression of activation markers and negative immune checkpoints. Single cell transcriptomic profiling demonstrated that dissociated TFC express numerous candidate molecules for mediating this suppressive activity, including CD40, E-Cadherin and TIGIT ligands. These ligands directly or through the generation of a suppressor population of DN T cells, and not the PD-1/PD-L1 axis, are most likely the responsible of TFC immunosuppressive activity. These results contribute to reveal the complex network of inhibitory mechanism that operate at the tissue level to restrain autoimmunity but also point to pathways, other that PD-1/PD-L1, that can contribute to tumor evasion.Copyright © 2023 Elsevier Ltd. All rights reserved.