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.

Graft rejection by the immune system is a major cause of transplant failure. Lifelong immunosuppression decreases the incidence of graft rejection; however, nonspecific immunosuppression results in increased susceptibly to infection and cancer. Regulatory T cells (Tregs), which suppress the activation of the immune system and induce tolerance, are currently under evaluation for use in clinical transplantation. Ex vivo expanded polyclonal Tregs that are introduced into transplant recipients alter the balance of T effector cells to Tregs; however, experimental data suggest that alloantigen-specific Tregs would be more effective at preventing graft rejection. We have developed a method to enrich alloantigen-specific human Tregs based on the coexpression of activation markers, CD69 and CD71. These Tregs could be readily expanded in vitro and demonstrated potent antigen-specific suppression. In a humanized mouse model of alloimmune-mediated injury of human skin grafts, alloantigen-specific Tregs resulted in a significant reduction in clinically relevant indicators of dermal tissue injury when compared with polyclonal Tregs, restoring a histology comparable to healthy skin. This method of human allospecific Treg selection should be scalable to the clinic. The improved in vivo efficacy of alloantigen-specific Tregs over polyclonal Tregs shown here suggests that generating “customized” Tregs with defined anti-donor allospecificities may improve current practice in clinical immunotherapy.

γδ T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human γδ cells in cutaneous homeostasis and pathology is poorly characterized. In this study we show in vivo evidence that human blood contains a distinct subset of pro-inflammatory cutaneous lymphocyte antigen (CLA) and C-C chemokine receptor (CCR) 6 positive Vγ9Vδ2 T cells, which is rapidly recruited into perturbed human skin. Vγ9Vδ2 T cells produced an array of pro-inflammatory mediators including IL-17A and activated keratinocytes in a TNF-α and IFN-γ dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vγ9Vδ2 T cells in psoriasis patients compared to healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vγ9Vδ2 T cells normalized after successful treatment with psoriasis-targeted therapy. Together with the increased presence of Vγ9Vδ2 T cells in psoriatic skin, this data indicates redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human pro-inflammatory γδ T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease.

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.