Abstract
Transforming growth factor (TGF)-βs are pluripotent cytokines with stimulatory and inhibitory properties for multiple types of immune cells. Analyses of genetic knockouts of each isoform of TGF-β have revealed differing expression patterns and distinct roles for the three mammalian isoforms of TGF-β. Considerable effort has been focused on understanding the molecular mechanisms of TGF-β1-mediated immune regulation, given its pivotal role in prohibiting systemic autoimmune disease. In recent years, functional similarities and differences between the TGF-β isoforms have delineated their distinct roles in the development of immunopathology and immune tolerance, with increased recent attention being focused on TGF-β3. In addition to the characteristic properties of each TGF-β isoform, recent progress has identified determinants of context-dependent functionality, including various cellular targets, cytokine concentrations, tissue microenvironments, and cytokine synergy, which combine to shape the physiological and pathophysiological roles of the TGF-βs in immunity. Controlling TGF-β production and signaling is being tested as a novel therapeutic strategy in multiple clinical trials for several human diseases. This review highlights advances in the understanding of the cellular sources, activation processes, contextual determinants, and immunological roles of TGF-β3 with comparisons to other TGF-β isoforms.
Highlights
The transforming growth factor (TGF)-β superfamily comprises more than 40 members, including the TGF-βs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, and nodals [1,2,3]
We focus on the molecular characteristics, immunological roles, and future possibilities of TGF-β3 in comparison to TGF-β1
We have previously reported that LAG3+ Tregs suppress systemic humoral immune responses in a TGF-β3-dependent manner [59], and that TGF-β3 production from LAG3+ Tregs is significantly reduced when the expression of transcriptional factors early growth response gene 2 (Egr2) and Egr3 is deficient or if Fas is mutated [59,60]
Summary
The transforming growth factor (TGF)-β superfamily comprises more than 40 members, including the TGF-βs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, and nodals [1,2,3]. TGF-β superfamily members share several biological functions, and possess specific or opposite functions under some conditions [1]. The TGF-βs are involved in a variety of biological functions in cellular activities, fibrosis, and immune responses, in addition to their crucial roles in tissue homeostasis [1]. TGF-β1 has been extensively investigated in immunity, because TGF-β1 is expressed predominantly by various immune cells [5], and deficiency of Tgfb results in fatal systemic autoimmune disease [6,7]. TGF-β2, is thought to play an insignificant role in the immune system due to its low expression in immune cells [8]. Recent accumulating evidence on the expression and function of TGF-β3 in immunity has revealed similarities and differences between TGF-β1 and TGF-β3 [9,10]. We focus on the molecular characteristics, immunological roles, and future possibilities of TGF-β3 in comparison to TGF-β1
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