# Tissue‐Resident Regulatory T Cells Expressing CD83 Maintain Local Homeostasis and Restrict Th2 Responses in Asthma

## TL;DR

CD83-expressing regulatory T cells in the lungs help maintain tissue balance and prevent asthma by controlling Th2 immune responses.

## Contribution

This study is the first to show that CD83 is essential for lung-resident Tregs to suppress Th2 responses and maintain tissue homeostasis during asthma.

## Key findings

- CD83-deficient Tregs are less differentiated but more activated, leading to unrestrained T-cell activation.
- CD83cKO mice show accelerated asthma progression due to Th2-biased immune responses and lung damage.
- CD83cKO Tregs are more responsive to IL-4, impairing their ability to control Th2 differentiation.

## Abstract

Non‐lymphoid tissue Tregs (NLT‐Tregs) are critical for tissue homeostasis, inflammation control, and induction of tissue repair. Recent single‐cell RNA sequencing data identified the expression of CD83 as part of an NLT‐Treg signature, which is an essential molecule for the stability and differentiation of lymphoid Tregs. However, the biological significance of CD83 expression for NLT Tregs has not yet been elucidated. The present study explores for the first time the role of CD83 expression by lung‐resident Tregs in the steady state and during asthma to understand its importance in barrier tissues. We evaluated the effect of Treg‐specific CD83 deletion (CD83cKO) on the lung‐resident T‐cell compartment and cytokine profile. CD83‐deficient lung Tregs are less differentiated but more activated, resulting in unrestrained T‐cell activation. Further, CD83cKO mice were challenged in an asthma model and showed an accelerated disease progression, driven by Th2‐biased T‐cell responses. CD83cKO Tregs exhibited 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 Th2 responses. Overall, our results highlight CD83 as a key player in tissue homeostasis and inflammatory responses, suggesting potential therapeutic implications for inflammatory disorders such as asthma.

Under steady‐state conditions, lung‐resident T cells from Treg‐specific mice (CD83cKO) are highly activated and secrete higher amounts of cytokines. During asthma, Th2‐responses derail in CD83cKO, leading to eosinophilia and lung damage. This effect relies on a destabilizing effect of IL‐4 on Tregs from CD83cKO mice.