Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren's Syndrome

• Published in: bioRxiv
• Main Authors: Wang, Yin-Hu, Li, Wenyi, McDermott, Maxwell, Son, Ga-Yeon, Maiti, George, Zhou, Fang, Tao, Anthony, Raphael, Dimitrius, Moreira, Andre L, Shen, Boheng, Vaeth, Martin, Nadorp, Bettina, Chakravarti, Shukti, Lacruz, Rodrigo S, Feske, Stefan
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 24.01.2024; Cold Spring Harbor Laboratory
• Edition: 1.1
• Subjects: Adoptive transfer; Autoantibodies; Calcium signalling; CD4 antigen; Clonal deletion; Effector cells; Flow cytometry; Immunological memory; Immunology; Immunoregulation; Inflammation; Lacrimal gland and Nasolacrimal duct; Leukocytes (mononuclear); Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoid tissue; Lymphopenia; Memory cells; Pathogenesis; Pathogenicity; Peripheral blood mononuclear cells; Salivary gland; Sjogren's syndrome; STIM1 protein; Transcriptomics; γ-Interferon; Th1 cells; interferon gamma; Calcium; STIM1; Sjogren’s Disease; STIM2; SOCE; Treg cells; Sjogren’s syndrome; Foxp3; Ca; single cell RNA-Seq
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.01.23.576314

Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 ( ), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells from mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation in mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells from mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4 T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.