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Skin Tregs rely on Gata3 to curb fibrosis: Hyperactive fibroblasts that overproduce extracellular matrix components are a root cause of tissue fibrosis, a shared feature of many chronic inflammatory diseases. Kalekar et al. found that depletion of regulatory T cells (Tregs) in mice resulted in increased skin fibrosis, prompting them to investigate the mechanisms by which skin-resident Tregs normally prevent excess fibroblast activation. RNA sequencing analysis of skin Tregs revealed preferential expression of transcription factors typically associated with TH2 differentiation, including GATA3 and IRF4. Genetic deletion of Gata3 in Tregs resulted in increases in TH2 cytokine production and excessive dermal fibrosis. These findings reveal that GATA3 expression by skin-resident Tregs is an adaptation to the cutaneous microenvironment that enables these specialized Tregs to maintain homeostatic control of fibroblast activity. See the related Focus by Bal and Stadhouders. At the center of fibrosing diseases is the aberrant activation of tissue fibroblasts. The cellular and molecular mechanisms of how the immune system augments fibroblast activation have been described; however, little is known about how the immune system controls fibroblast function in tissues. Here, we identify regulatory T cells (Tregs) as important regulators of fibroblast activation in skin. Bulk cell and single-cell analysis of Tregs in murine skin and lungs revealed that Tregs in skin are transcriptionally distinct and skewed toward T helper 2 (TH2) differentiation. When compared with Tregs in lung, skin Tregs preferentially expressed high levels of GATA3, the master TH2 transcription factor. Genes regulated by GATA3 were highly enriched in skin "TH2 Treg" subsets. In functional experiments, Treg depletion resulted in a preferential increase in TH2 cytokine production in skin. Both acute depletion and chronic reduction of Tregs resulted in spontaneous skin fibroblast activation, profibrotic gene expression, and dermal fibrosis, all of which were exacerbated in a bleomycin-induced murine model of skin sclerosis. Lineage-specific deletion of Gata3 in Tregs resulted in an exacerbation of TH2 cytokine secretion that was preferential to skin, resulting in enhanced fibroblast activation and dermal fibrosis. Together, we demonstrate that Tregs play a critical role in regulating fibroblast activation in skin and do so by expressing a unique tissue-restricted transcriptional program that is mediated, at least in part, by GATA3. [ABSTRACT FROM AUTHOR]

The article presents a study on immunophenotyping on skin and blood to determine the severity of skin symptoms of toxic epidermal necrolysis (TEN), a cutaneous adverse drug reaction. It discusses the characterization of TEN, findings on the main leucocytes in TEN blisters at the acute phase based on mass cytometry, and the expansion of unique CDR3 clonotypes in blister cells.

Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8 + T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase. Deep T cell receptor (TCR) repertoire sequencing identified massive expansion of unique CDR3 clonotypes in blister cells. The same clones were highly expanded in patient's blood, and the degree of their expansion showed significant correlation with disease severity. By transducing α and β chains of the expanded clonotypes into a TCR-defective cell line, we confirmed that those cells were drug specific. Collectively, these results suggest that the relative clonal expansion and phenotype of skin-recruited CTLs condition the clinical presentation of cutaneous adverse drug reactions., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)