IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjögren’s syndrome

Abstract

Increased numbers of T follicular helper (Tfh) cells have been implicated in the development of autoimmune diseases including primary Sjögren's syndrome (pSS), but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear. Here, we first found negative correlations between IL-10 + regulatory B (Breg) cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjögren's syndrome (ESS). Moreover, we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice. In culture, IL-10 suppressed human and murine Tfh cell differentiation by promoting STAT5 phosphorylation. By using an adoptive transfer approach and two-photon live imaging, we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2−/− mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2−/− mice transferred with wild-type B cells. In ESS mice, CD19 + CD1d hi CD5 + Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation. Consistently, CD19 + CD24 + CD38 hi Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion. Furthermore, the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice. Together, these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development.

Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

“…Given the role of regulatory B cells in restricting cellular responses, we propose this B cell defect could contribute to the relapsing and remitting nature of the disease. Moreover, it has been shown that B cell-derived IL-10 is important in T follicular helper organization, and restricting excessive antibody responses via interaction with Tfh cells 56 , 57 . It is therefore tempting to speculate that these patients generate inappropriately inflammatory B-cell responses in lymphoid organs.…”

Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

“…Similarly, IL-7-dependent activation of STAT5 contributes to Bcl6 repression [ 60 ]. The latest research shows that IL-10 suppresses the differentiation of Tfh cells in human and mice by promoting STAT5 phosphorylation [ 61 ]. He et al [ 62 ] demonstrate that the secreted protein extracellular matrix protein 1 induced by IL-6 and IL-21 in Tfh cells promotes the differentiation of Tfh cells by downregulating the level of STAT5 phosphorylation and upregulating Bcl6 expression.…”

Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus

“…Recently, we reported a novel function of Bregs in modulating Tfh generation in patients with primary Sjögren’s syndrome (pSS) [128]. The decreased Bregs and increased Tfh cells were inversely correlated in both pSS patients and mice with experimental Sjögren’s syndrome (ESS).…”