Regulatory T cells promote innate inflammation after skin barrier breach via TGF-β activation

Abstract

Regulatory T cells (Tregs) use multiple mechanisms to attenuate inflammation and prevent autoimmunity. Tregs residing in peripheral (i.e., nonlymphoid) tissues have specialized functions; specifically, skin Tregs promote wound healing, suppress dermal fibrosis, facilitate epidermal regeneration, and augment hair follicle cycling. Here, we demonstrated that skin Tregs were transcriptionally attuned to interact with their tissue environment through increased expression of integrin and TGF-β pathway genes that influence epithelial cell biology. We identified a molecular pathway where skin Tregs license keratinocytes to promote innate inflammation after skin barrier breach. Using a single-cell discovery approach, we identified preferential expression of the integrin αvβ8 on skin Tregs. Upon skin injury, Tregs used this integrin to activate latent TGF-β, which acted directly on epithelial cells to promote CXCL5 production and neutrophil recruitment. Induction of this circuit delayed epidermal regeneration but provided protection from Staphylococcus aureus infection across a compromised barrier. Thus, αvβ8-expressing Tregs in the skin, somewhat paradoxical to their canonical immunosuppressive functions, facilitated inflammation acutely after loss of barrier integrity to promote host defense against infection.

The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity

“…Tregs in soft tissue have also been found to enhance the regenerative process, mainly by enforcing immune tolerance and suppressing excessive inflammation [ 194 ]. For instance, Moreau et al [ 195 ] have reported that Treg-derived amphiregulin induces tissue-resident T cell proliferation upon injury, thus leading to an immune-suppressive microenvironment and tissue regeneration (Fig. 2 a).…”

Nonresolving inflammation redux

“…Recent evidence adds new examples and mechanisms. Regulatory T (Treg) cells are indispensable for resolution of inflammation ( Hu et al., 2021 ), yet intradermal Treg cells promoted epidermal inflammation in wounded skin by driving keratinocytes to produce neutrophil-recruiting chemokines ( Moreau et al., 2021 ). Platelets helped resolve the pulmonary inflammation associated with bacterial pneumonia in mice by physically trapping Treg cells in the lung and inducing a pro-resolution transcriptional program in macrophages ( Rossaint et al., 2021 ).…”

Computational exploration of cellular communication in skin from emerging single-cell and spatial transcriptomic data

“…CellPhoneDB analysis of mouse scRNA-seq data predicted ephrin signaling-mediated epithelial-mesenchymal crosstalk that enables mesenchymal competence for regeneration in skin wound healing[ 55 ]. Another application of CellPhoneDB to skin injury revealed that αvβ8 expression in skin Tregs helps to activate TGF-β in neighboring keratinocytes, which act directly on epithelial cells to promote CXCL5 production and neutrophil recruitment, suggesting that αvβ8-expressing Tregs contributes to innate inflammation and delayed epidermal repair after inducing skin injury [ 56 ]. In addition, NicheNet analysis was applied to identify the signals driving the response of OTULIN-deficient keratinocytes to inflammation [ 57 ].…”