Thyroid cells from normal and autoimmune thyroid glands suppress T lymphocytes proliferation upon contact revealing a new regulatory inhibitory type of interaction independent of PD1/PDL1. Issue 136 (April 2023)

• Record Type: Journal Article
• Authors: Álvarez-Sierra, Daniel; Sánchez-Gaona, Nerea; Cruz Cobo, María; Escriche, Alba; Abad, María; Gómez-Brey, Aroa; Bello, Irene; Caubet, Enric; González, Óscar; Zafón, Carles; Iglesias, Carmela; Moreno, Pablo; Petit, Anna; Fernández-Sanmartín, Marco Antonio; Martínez-Gallo, Mónica; Pujol-Borrell, Ricardo
• Is Part Of: Journal of autoimmunity. Issue 136(2023)
• Publication Date: 2023-04
• Subjects: Thyroid autoimmunity -- Peripheral tolerance -- Adaptative immunity -- T lymphocytes -- Immune checkpoints -- PD-1/PD-L1; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2023.103013
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: Cultured primary thyroid follicular cells (TFCs) spontaneously express PD-L1. Autologous primary thyrocytes reduce T cell proliferation in vitro . Proliferation inhibition is contact dependent, but is not mediated by PD-L1. scRNA-seq allowed identification of candidate inhibitory molecules.