In:
Science Immunology, American Association for the Advancement of Science (AAAS), Vol. 4, No. 39 ( 2019-09-13)
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 (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 H 2) differentiation. When compared with T regs in lung, skin T regs preferentially expressed high levels of GATA3, the master T H 2 transcription factor. Genes regulated by GATA3 were highly enriched in skin “T H 2 T reg ” subsets. In functional experiments, T reg depletion resulted in a preferential increase in T H 2 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 H 2 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.
Type of Medium:
Online Resource
ISSN:
2470-9468
DOI:
10.1126/sciimmunol.aaw2910
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2019
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