MassIVE MSV000098194

Partial Public PXD065015

IL17-producing gamma T cells modulate murine tissue fibrosis through stromal cell interactions

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Description

Tissue injury responses are governed by dynamic immune-stromal crosstalk that can promote productive tissue repair or drive dysregulated extracellular matrix (ECM) production and aberrant vascular remodeling, culminating in fibrosis. Here, we investigate how gamma T cells interact with stromal cells to shape tissue fibrosis using a preclinical model of the biomaterial foreign body response that induces a reproducible, dense fibrotic encapsulation. A mixed population of tissue-resident and migratory gamma delta T cells, consisting of type-1 (gamma delta IFN gamma) and multiple type-17 (gamma delta 17) effector subsets, accumulated at the biomaterial implantation site during the early inflammatory phase of wound healing. While the gamma delta IFN gamma later contracted as tissue fibrosis progressed, the activated gamma delta 17 persisted and served as a dominant source of interleukin (IL)-17. Aging and exposure to a high-fat diet, both factors associated with chronic inflammation and pathological fibrosis, further heightened the gamma delta 17 response. The gamma delta 17 secreted bioactive factors that stimulated fibroblast expression of pro-inflammatory and collagen genes in a Transwell co-culture assay. Computational inference of intercellular communication further linked cytokines and growth factors expressed by gamma delta T cells to the activation of fibroblast and endothelial cell transcription factors involved in ECM remodeling and vascular development, respectively. The elimination of gamma delta T cells with a TCR delta knockout strain resulted in differential expression of ECM and skeletal muscle components as well as altered blood vessel structure within the fibrotic matrix. Altogether, our results propose that signaling from gamma delta T cells can affect stromal cell phenotypes, ultimately influencing the composition and vascularity of fibrotic tissue. [doi:10.25345/C5W669N1N] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: fibrosis ; DIA-MS ; proteomics ; muscle ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Birgit Schilling, Buck Institute, USA
Submitting User: cking
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