UCSF

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 (T_regs) as important regulators of fibroblast activation in skin. Bulk cell and single-cell analysis of T_regs in murine skin and lungs revealed that T_regs in skin are transcriptionally distinct and skewed toward T helper 2 (T_H2) differentiation. When compared with T_regs in lung, skin T_regs preferentially expressed high levels of GATA3, the master T_H2 transcription factor. Genes regulated by GATA3 were highly enriched in skin "T_H2 T_reg" subsets. In functional experiments, T_reg depletion resulted in a preferential increase in T_H2 cytokine production in skin. Both acute depletion and chronic reduction of T_regs 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 T_regs resulted in an exacerbation of T_H2 cytokine secretion that was preferential to skin, resulting in enhanced fibroblast activation and dermal fibrosis. Together, we demonstrate that T_regs 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.