Regulatory T cells in skin are uniquely poised to suppress profibrotic immune responses

Abstract

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.

Tissue regulatory T cells

“…Treg-specific deletion of GATA3 also manifests in polymorphonuclear cell infiltrate, as well as IL-5 and IL-13 producing CD8 + T cells in skin. 101,102 These findings imply that skin Tregs (or at least a subset thereof) maintain skin homeostasis via regulation of Th2 immunity.…”

“…101 At the single-cell level, Gata3 transcript is most abundant in murine skin Tregs, relative to other Th lineage transcription factors Rorc and Tbx21, suggesting that skin Tregs may be skewed towards Th2 regulation. 101 Conditional deletion of GATA3 in Tregs (Foxp3 YFP-Cre Gata3 fl/fl ) results in Type 2 associated skin inflammation, accompanied by a reduction in Treg abundance and activation. Treg-specific deletion of GATA3 also manifests in polymorphonuclear cell infiltrate, as well as IL-5 and IL-13 producing CD8 + T cells in skin.…”

“…These include epidermal hyperplasia, the abundance of other skin-resident immune cells, and the production of the pro-inflammatory cytokines IFN-c, TNF-a and IL-17. 92,101 However, Treg depletion up-regulates the Th2 cytokines IL-13 and IL-4. 101 At the single-cell level, Gata3 transcript is most abundant in murine skin Tregs, relative to other Th lineage transcription factors Rorc and Tbx21, suggesting that skin Tregs may be skewed towards Th2 regulation.…”

“…92,101 However, Treg depletion up-regulates the Th2 cytokines IL-13 and IL-4. 101 At the single-cell level, Gata3 transcript is most abundant in murine skin Tregs, relative to other Th lineage transcription factors Rorc and Tbx21, suggesting that skin Tregs may be skewed towards Th2 regulation. 101 Conditional deletion of GATA3 in Tregs (Foxp3 YFP-Cre Gata3 fl/fl ) results in Type 2 associated skin inflammation, accompanied by a reduction in Treg abundance and activation.…”

ICOS signaling limits regulatory T cell accumulation and function in visceral adipose tissue

“…More recent work highlights additional roles for specialized subsets of tissue-specific T R in tissue repair and homeostasis. For example, Areg + T R expand in skeletal muscle and the lungs in response to injury and are required for proper tissue repair (4,5), whereas T R within hair follicles and skin are essential for hair generation and keeping profibrotic processes in check, respectively (6,7). A transcriptionally unique population of T R are found in the visceral adipose tissue (VAT) of both mice and humans, and these T R regulate adipose inflammation and preserve metabolic homeostasis as demonstrated by loss-and gain-of-function experiments (8)(9)(10)(11).…”