T follicular helper 1 cells in blood potentially mirror salivary gland-infiltrating T cells in Sjögren’s disease

Abstract

Understanding the intricate relationship between peripheral blood immune profiles and the inflammatory environment within affected tissues is pivotal for uncovering mechanisms driving autoimmune diseases. This study aimed to characterize CD4+ T cell subsets in peripheral blood that mirror the immunological activation of labial salivary glands (LSG) infiltrating T cells in primary Sjögren’s disease (pSjD). Using multicolor flow cytometry and T cell receptor (TCR) sequencing, we identified CXCR3+CXCR5+ T follicular helper 1 (Tfh1) cells as significantly elevated in the circulation of pSjD patients and even more prominently increased in the LSG, with blood PD-1+ICOS+ Tfh1 cells positively correlating with titers of antinuclear, anti-SS-A, and anti-SS-B antibodies. In contrast, CXCR3+CXCR5− Th1 cells were enriched in LSG but reduced in circulation. TCR analysis demonstrated that circulating Tfh1 cells shared a notable clonal similarity with LSG T cells. In the LSG, cytokines such as IL-6, IL-12, IL-21, and TGF-β were upregulated, with TGF-β and TCR recognition promoting Tfh1 differentiation. This microenvironment led to increased production of IL-2, TNF-α, and IL-21, promoting the expansion of CD19+CD38+ B cells. These findings support the notion that circulating activated Tfh1 cells partially mirror glandular T cell activation and highlight TGF-β as a driver of Tfh1 differentiation, presenting a potential therapeutic target.