RORγt antagonist improves Sjögren's syndrome‐like sialadenitis through downregulation of CD25

Abstract

Objective We reported previously that T‐cell‐specific RORγt‐transgenic mice under human CD2 promoter (RORγt‐Tg mice) developed severe spontaneous Sjögren's syndrome (SS)‐like sialadenitis, induced by RORγt‐overexpressing CD4+T cells and reduced regulatory T cells. The purpose of this study was to clarify the effectiveness and mechanisms of action of A213, a RORγt antagonist, in RORγt‐Tg mice with SS‐like sialadenitis. Methods Six‐week‐old RORγt‐Tg mice were administered orally of A213 or phosphate‐buffered saline every 3 days for 2 weeks. We analyzed saliva volume, histopathology of salivary glands, populations of T cells in splenocytes and cervical lymph nodes (cLNs), and the protein expression levels of CD69 on CD4+CD25+Foxp3− and CD4+CD25+Foxp3+ cells in cLNs. We also investigated in vitro the potential immunomechanisms of action of A213. Results A213 significantly increased saliva volume, reduced mononuclear cell infiltration in salivary glands, and reduced the focus score of sialadenitis. Analysis of the immunomechanisms using cLNs showed A213 significantly reduced the proportion of CD4+CD25+/CD4+ T cells and the protein expression levels of CD69 on CD4+CD25+Foxp3− cells. In vitro experiments showed that A213 suppressed CD25 expression on CD4+ T cells and reduced IL‐2 production from CD4+ T cells derived from RORγt‐Tg mice. Conclusion A213 improves SS‐like sialadenitis through the inhibition of CD4+CD25+ cells in cLNs.

Secreted factors from dental pulp stem cells improve Sjögren’s syndrome via regulatory T cell-mediated immunosuppression

“…The presence of activated T cells (CD3 + CD25 + or CD3 + CD69 + cells) and Th cells (CD4 + CD25 + or CD4 + CD69 + cells) was investigated as described previously [35,36]. Moreover, RORγ-transgenic mice, an established SS-like sialadenitis mice model, were reported to induce the expression of IL-2-mediated CD25 and CD69 on CD4 + T cells [37].…”

Resolvin E1 Regulates Th17 Function and T Cell Activation

“…Our work demonstrated that the stimulation of naïve CD4 + T cells with either Pam 3 CSK 4 in co-cultures or Th17 polarizing reagents resulted in the most profound increase in CD25 expression; RvE1 significantly decreased this under T h 17 polarizing conditions. This finding was in parallel with a significantly reduced IL-2 cytokine secretion by T cells under the same conditions by the RvE1, which may suggest that RvE1 suppressed IL-2 secretion leading to a decrease of CD25 expression ( 66 ). CD4 + CD25 + T cells are known as “natural suppressor cells,” showing anergic, suppressing functions by inhibiting transcription of IL-2 via TCR, Exposing to antigen stimulation or polyclonal T cell receptor stimulation activates these cells (CD4 + CD25 + ) to mediate their suppressive functions ( 67 , 68 ), which may be the reason for increased CD4 + CD25 + T cell populations under Th17 polarizing conditions and DC-mediated Th17 polarization.…”

One year in review 2021: Sjögren's syndrome

“…Treatment of SS animal models demonstrated that administering an analogue of B7-H4 -a co-stimulatory molecule involved in the promotion of Treg cells activity and whose blockade is known to worsen multiple models of autoimmune diseases -was able to reduce lymphocyte infiltration in salivary glands and an expansion of Treg cells (110). Disease improvement was also demonstrated by inhibiting bone morphogenetic protein (BMP)-6, highmobility group box (HMGB)1 (which have both been associated to reduced salivary secretion (110,111)), and transcription factor RAR-related orphan receptor (ROR)γt (112). Some in vitro evidence suggests that Janus kinase (JAK) inhibitors may be effective in SS by modulating DNA hydromethylation induced by IFNs and reactive oxygen species (113).…”