Regulatory T cells control fibroblast activation in skin to suppress the pathogenesis of tissue fibrosis

The activity and function of regulatory T cells (Tregs) largely depends on the tissue in which they reside. Recent research has identified that Tregs in the skin are primed to control the pathogenesis of tissue fibrosis by expressing a unique transcriptional signature that supports the effective suppression of type 2 immune responses.

Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. Source: NIAID

By Sree Yellanki

Many fibrosing diseases such as sclerosis, idiopathic pulmonary fibrosis, and end-stage liver disease are associated with the unusual activation of tissue fibroblasts, which is a type of cell that synthesizes the extracellular matric and collagen. However, little is known about how the immune system conducts fibroblast activation in tissues. Recent research has found that regulatory T cells (Tregs) are important regulators of fibroblast activation and the pathogenesis of tissue fibrosis in the skin.

Tregs are composed of different subsets which have different mechanisms depending on which tissue they reside in. Whole transcriptome RNAseq performed on live cells that were purified from skin and skin-draining lymph nodes revealed that Tregs in skin express high levels of TH2-assoicated genes. Genes associated with TH2 included the master transcription factor GATA3. Furthermore, a Gene Set Enrichment Analysis also showed that a significant number of genes are regulated by GATA3 in skin Tregs compared to the skin-draining lymph nodes. For example, Amphiregulin, a gene regulated by GATA3 and involved in communicating with Tregs was found heavily in skin clusters of Tregs. Additionally, when compared to Tregs isolated from healthy lungs, GATA3 expression was enhanced in skin Tregs. Overall, these results indicate that Tregs in skin cells are TH2 skewed and differentiation is largely driven by GATA3.

Results show that Tregs in skin are TH2 skewed, so in order to determine whether these cells are capable of suppressing type 2 immune responses, mice were injected with Diphtheria toxin to deplete Tregs in both skin and lung tissue. There was a notable increase in the expression of Interleukin 13, a profibrotic cytokine involved in TH2 responses in humans, in skin but not in lung tissue. Thus, Tregs in skin were found to be important for the regulation of TH2 immune responses, in part through controlling the expression of Interleukin 13. Since Tregs in skin attenuate TH2 responses, TH2 cytokines such as interleukin 13 may result in the pathogenesis of tissue fibrosis. Furthermore, experiments in which mice were chronically depleted of Tregs showed increased expressions of the TGF-B pathway as well as of the cytokines IL-13 and IL-5, further demonstrating that a reduction in Tregs is associated with an increased TH2 response and enhanced skin fibrosis.

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Since the expression of genes regulated by GATA3 is significantly enriched in Tregs that reside in the skin, this transcription factor may be largely responsible for the anti-fibrotic effects of this T cell subset. GATA3 mediates a transcriptional program in Tregs that allows the cells to suppress TH2 immune responses and regulate the activation and behavior of dermal fibroblasts and ultimately skin fibrosis through the suppression of profibrotic immune responses.

Thus, any defects in Treg function may result in fibrosis. However, more studies are required to determine the various roles and pathways Tregs use to control fibroblast activation. Since the activity of Tregs may depend upon tissue type, it is possible that these cells use different mechanisms to regulate fibroblasts in various locations. More focus should be spent on the function of Tregs since understanding their function can support the prevention and treatment of fibrosis in tissues.

Kalekar LA, Cohen JN, Prevel N, et al. (2019) Regulatory T cells in skin are uniquely poised to suppress profibrotic immune responses. Science Immunology, 4(39), eaaw2910. DOI: 10.1126/sciimmunol.aaw2910