Expression of CD83 in tissue-resident regulatory T cells maintains local homeostasis and restricts effector cells in allergic asthma

Abstract

Abstract Non-lymphoid tissue Tregs (NLT-Tregs) are critical for tissue homeostasis, inflammation control, and induction of mucosal repair. Recent single-cell RNA sequencing data identified expression of CD83 as part of a NLT-Treg signature, however its biological significance for this specialized Tregs was not yet fully understood. In our previous investigations, we found that conditional deletion of CD83 (CD83cKO) disrupts stability and differentiation of lymphoid Tregs and exacerbates autoimmune responses. The present study explores for the first time the role of CD83 expression by lung-resident Tregs to understand its importance in barrier tissues. We report that CD83-deficient lung Tregs are less differentiated but more activated, resulting in unrestrained T cell activation. Furthermore, using an allergic asthma model, CD83cKO mice showed an accelerated disease progression, with augmented eosinophilic inflammation, driven by Th2-biased T cell responses. CD83cKO Tregs exhibited an enhanced responsiveness to IL-4, leading to insufficient control of Th2-differentiation from naïve T cells. These findings underscore the pivotal role of CD83 in the NLT-Treg-mediated modulation of inflammation, especially in the context of Th2 responses. Overall, our results highlight CD83 as a key player in maintaining tissue homeostasis and modulating inflammatory responses, suggesting potential therapeutic implications for inflammatory disorders such as asthma.