Summary The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of Tregs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.

Summary The skin is a site of constant dialogue between the immune system and commensal bacteria. However, the molecular mechanisms that allow us to tolerate the presence of skin commensals without eliciting destructive inflammation are unknown. Using a model system to study the antigen-specific response to S. epidermidis, we demonstrated that skin colonization during a defined period of neonatal life was required to establish immune tolerance to commensal microbes. This crucial window was characterized by an abrupt influx of highly activated regulatory T (Treg) cells into neonatal skin. Selective inhibition of this Treg cell wave completely abrogated tolerance. Thus, the host-commensal relationship in the skin relied on a unique Treg cell population that mediated tolerance to bacterial antigens during a defined developmental window. This suggests that the cutaneous microbiome composition in neonatal life is crucial in shaping adaptive immune responses to commensals, and disrupting these interactions may have enduring health implications.

Foxp3-expressing regulatory T cells (Tregs) reside in tissues where they control inflammation and mediate tissue-specific functions. The skin of mice and humans contain a large number of Tregs; however, the mechanisms of how these cells function in skin remain largely unknown. Here, we show that Tregs facilitate cutaneous wound healing. Highly activated Tregs accumulated in skin early after wounding and specific ablation of these cells resulted in delayed wound re-epithelialization and kinetics of wound closure. Tregs in wounded skin attenuated IFNγ production and pro-inflammatory macrophage accumulation. Upon wounding, Tregs induce expression of the epidermal growth factor receptor (EGFR). Lineage-specific deletion of EGFR in Tregs resulted in reduced Treg accumulation and activation in wounded skin, delayed wound closure and increased pro-inflammatory macrophage accumulation. Taken together, our results reveal a novel role for Tregs in facilitating skin wound repair and suggest that Tregs utilize the EGFR pathway to mediate these effects.

Background: Dupilumab is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials. Objective:We sought to assess the effectiveness and safety of dupilumab in adults with AD in a real-life French multicenter retrospective cohort.Methods: Patients were included between March 2017 and April 2018. Efficacy outcomes were collected both at baseline and three months (M3), when available, including SCORAD (Scoring Atopic Dermatitis) and EASI (Eczema Area and Severity Index) scores. Adverse events (AE) were recorded at the follow-up. Results:We included 241 patients. The median follow-up time was 3.8±3.7 months. SCORAD75 and EASI75 were achieved in 27/163 (16.6%) and 40/82 (48.8%) patients, respectively. The median SCORAD and EASI at M3 were significantly lower compared with baseline (25±21 vs 56±27.4, p<10 -9 and 4.1±6.8 vs 17.9±15.4, p<10 -9 , respectively).Conjunctivitis was reported in 84/241 (38.2%) patients. The proportion of eosinophilia (>500/mm 3 ) during follow-up (57%) was higher than at baseline (33.7%) (n=172, p<10 -6 ).Dupilumab was stopped in 42 cases, 27 of which were due to an AE. Limitations:No control group, missing data. Conclusion:This real-life study demonstrated results similar to clinical trials, with regard to dupilumab effectiveness, but revealed a higher frequency of conjunctivitis and eosinophilia.