Abstract
Fibrosis is the extensive deposition of fibrous connective tissue, and it is characterized by the accumulation of collagen and other extracellular matrix (ECM) components. Fibrosis is essential for wound healing and tissue repair in response to a variety of triggers, which include infection, inflammation, autoimmune disorder, degenerative disease, tumor, and injury. Fibrotic remodeling in various diseases, such as liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc), and graft-versus-host disease (GVHD), can impair organ function, causing high morbidity and mortality. Both innate and adaptive immunity are involved in fibrogenesis. Although the roles of macrophages in fibrogenesis have been studied for many years, the underlying mechanisms concerning the manner in which T cells regulate fibrosis are not completely understood. The T cell receptor (TCR) engages the antigen and shapes the repertoire of antigen-specific T cells. Based on the divergent expression of surface molecules and cell functions, T cells are subdivided into natural killer T (NKT) cells, γδ T cells, CD8+ cytotoxic T lymphocytes (CTL), regulatory T (Treg) cells, T follicular regulatory (Tfr) cells, and T helper cells, including Th1, Th2, Th9, Th17, Th22, and T follicular helper (Tfh) cells. In this review, we summarize the pro-fibrotic or anti-fibrotic roles and distinct mechanisms of different T cell subsets. On reviewing the literature, we conclude that the T cell regulations are commonly disease-specific and tissue-specific. Finally, we provide perspectives on microbiota, viral infection, and metabolism, and discuss the current advancements of technologies for identifying novel targets and developing immunotherapies for intervention in fibrosis and fibrotic diseases.
Highlights
As a leading cause of mortality, fibrotic diseases can occur in virtually every organ and tissue
What is the initial trigger of fibrosis? How do we identify risk factors leading to a severe fibrotic disease? How do we utilize T cells in other fibrosis-related narratives? The pandemic of 2019 coronavirus disease COVID-19, caused by the SARS-CoV-2 virus infection, has caused worldwide mortality [144]
COVID-19 is accompanied by fibrosis [145, 146], and is dangerous for patients with pulmonary fibrotic diseases including cystic fibrosis [147]
Summary
As a leading cause of mortality, fibrotic diseases can occur in virtually every organ and tissue. Numerous studies have demonstrated that the immune response plays an essential role in fibrosis and fibrotic diseases. Wynn et al previously used IL-12 for treating Schistosoma mansoni infection in mice This inhibited Th2-dominated immune response by elevating Th1 cytokine expression and drastically ameliorated fibrosis [86]. IFNγ production up-regulates the expression of matrix metalloproteinases (MMPs), including MMP-2, MMP-7, MMP9, and MMP-13, to degrade ECM components This proteolytic activity helps alter ECM remodeling and ameliorates fibrosis [87]. Th1 cells and cytokine IFNγ are not always anti-fibrotic On the contrary, they can play a harmful role in bone regeneration [88], liver injury [89], and fibrotic diseases [30, 31]. Biliary fibrosis in murine sclerosing cholangitis A. fumigatus-induced lung fibrosiss IRI S. japonicum infection SSc GvHD PBC IPF Silica-induced lung fibrosis IPF CCl4 Cystic fibrosis CVB3 infection Cystic fibrosis CCl4 MCD diet GVHD Thyroid epithelial cell fibrosis Bleomycin-induced pulmonary fibrosis UUO Bleomycin-induced pulmonary fibrosis TAA, CCl4 α-GalCer, CCl4 NASH CCl4 PBC NASH CCl4 CCl4, MCD diet ILDs IPF Cystic fibrosis CCl4, MCD diet Bleomycin-induced pulmonary fibrosis
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