Debilitating fibrotic diseases such as scleroderma, idiopathic pulmonary fibrosis, and end-stage liver disease are associated with the unusual activation of tissue fibroblasts, a type of cell that synthesizes the extracellular matrix that is present in normal tissue. However, little is known about how the immune system regulates the activation of fibroblasts within tissues.
Recent research has found that regulatory T cells (Tregs), an immunosuppressive white blood cell subset, are important regulators of fibroblast activation and tissue fibrosis in the skin. Lokesh Kalakar and his team from UCSF explored mechanisms regulating the involvement of Tregs in tissue fibrosis and also provided insight into Treg biology.
The scientists found that Treg biology varies based on the tissue in which they reside. Whole transcriptome RNAseq performed on live cells purified from the skin and skin-draining lymph nodes revealed that Tregs present in the skin expressed high levels of the transcription factor GATA3, which is classically associated with a different subset of T cells known as TH2 cells that are often associated with allergic responses.
Interestingly, GATA3 was shown to be more strongly involved in the regulation of gene expression in skin Tregs as compared to those present in skin-draining lymph nodes or healthy lungs. Amphiregulin, a gene regulated by GATA3, was found heavily in skin clusters of Tregs but not by Tregs in other tissues.
Since Tregs in the skin were found to have a TH2 bias, the researchers sought to determine whether these cells are capable of suppressing type 2 immune responses. After injecting mice with Diphtheria toxin to deplete Tregs in both skin and lung tissue, the researchers identified a notable increase in the expression of Interleukin 13, a pro-fibrotic 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 and tissue-specific availability of Interleukin 13.
Experiments in which mice were chronically depleted of Tregs showed increased expression of the TGF-B pathway as well as of the cytokines IL-13 and IL-5, indicating that a reduction in Treg populations is associated with an increased TH2 response that could exacerbate skin fibrosis.
Since the expression of genes regulated by GATA3 is significantly enriched in Tregs that reside in the skin, this transcription factor may be important to the anti-fibrotic activity 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, ultimately contributing to the regulation of skin fibrosis through the suppression of profibrotic immune responses.
While defects in Treg function could result in fibrosis, more studies are required to determine the precise mechanisms that 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. Perhaps a greater effort should be dedicated to interrogating the function of Tregs since understanding their biology could support the prevention and treatment of debilitating fibrotic diseases.
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