Wang Yin-Hu, Li Wenyi, McDermott Maxwell, Son Ga-Yeon, Maiti George, Zhou Fang, Tao Anthony Y, Raphael Dimitrius, Moreira Andre L, Shen Boheng, Vaeth Martin, Nadorp Bettina, Chakravarti Shukti, Lacruz Rodrigo S, Feske Stefan
Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA.
Sci Transl Med. 2024 Dec 18;16(778):eado4856. doi: 10.1126/scitranslmed.ado4856.
Sjögren's disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (T) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of T cells depend on store-operated Ca entry (SOCE), which is mediated by ORAI1 Ca channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3 T cell-specific deletion of and develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (T1) and interferon (IFN) signaling. CD4 T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ-dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4 T cell-induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4 T cells from patients with SjD, which indicate enhanced T1 but reduced memory T cell function. Together, our study provides evidence for a critical role of dysfunctional T cells and IFN-γ-producing T1 cells in the pathogenesis of SjD.
干燥综合征（SjD）是一种自身免疫性疾病，其特征为进行性唾液腺和泪腺功能障碍、炎症及破坏，以及腺体外表现。SjD与自身反应性B细胞和T细胞相关，但其病理生理学仍未完全阐明。调节性T（Treg）细胞异常在多种自身免疫性疾病中出现，但其在SjD中的作用尚不明确。我们之前已表明，T细胞的功能和发育依赖于储存式钙内流（SOCE），这由ORAI1钙通道及基质相互作用分子1（STIM1）和STIM2介导。在此，我们发现Foxp3在T细胞中特异性缺失的小鼠会出现符合人类SjD所有分类标准的表型。突变小鼠的唾液腺和泪腺存在炎症，其特征为强烈的淋巴细胞浸润以及以辅助性T细胞1（Th1）和干扰素（IFN）信号为主导的转录特征。来自突变小鼠的CD4 + T细胞足以以IFN-γ依赖的方式诱导类似SjD的疾病。用JAK1/2抑制剂巴瑞替尼抑制IFN信号可减轻小鼠中CD4 + T细胞诱导的SjD。这些发现与SjD患者CD4 + T细胞的转录谱一致，后者表明Th1功能增强但记忆性T细胞功能降低。总之，我们的研究为功能失调的T细胞和产生IFN-γ的Th1细胞在SjD发病机制中的关键作用提供了证据。
