Regulation and role of transforming growth factor-β in immune tolerance induction and inflammation

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Transforming growth factor-β (TGF-β) is known to mediate pleiotropic functions both inside and outside the immune system. Recent progress in this field underlines the role of TGF-β in regulatory T (Treg) cells, where it participates in both suppression and differentiation. In addition, recent information highlights the role of TGF-β in repair responses that lead to matrix deposition and tissue remodelling. Many chronic inflammatory diseases, such as asthma, profit from the suppression of specific immune responses by TGF-β; however, TGF-β-mediated tissue remodelling can be a serious complication in such diseases.

Introduction

The chronic inflammatory immune responses observed in allergy and autoimmune disorders, as well as in infectious diseases and transplantation, represent the combined efforts of the innate and specific immune system to protect an organism from losing the function of the affected organ. The specific immune system — in particular, the T cells — has a key role in maintaining peripheral tolerance not only to autologous and commensal antigens, but also to harmless environmental proteins. Our current understanding of this thymus-independent peripheral tolerance is that the commitment of antigen-naïve T cells to some effector phenotypes such as T helper type 1 (Th1) or type 2 (Th2) cells is accompanied by the generation of regulatory T (Treg) cells that are capable of suppressing effector T cells. Effector cells are memory T cells that constitute the ‘immunological memory’; that is, they carry antigen-related information on the quality of the response and thereby determine the extent and/or duration of antigen-specific immune responses.

Most immunological reactions are self-limited, and Treg cells are now recognized as a central factor in the silencing of specific immune reactions. Silencing is particularly important in those diseases from which the immune systems fails to recover and that consequently proceed into chronic conditions. Recovery after inflammatory reactions has to compensate for cell lysis and lateral tissue damage, and has to restore the function of the affected organ; however, this part of the recovery response represents a major complication in chronic disease because it carries the risk of organ failure. An important cytokine in the recovery response is transforming growth factor-β (TGF-β), which plays a key role by mediating both the suppression of Treg cell generation and the repair of damaged tissues.

Although many chronic inflammatory diseases profit from the suppression of immunological responses by TGF-β, tissue remodelling mediated by TGF-β can be a serious complication in such diseases. In this review, we summarize recent advances in our understanding of both immunosuppression and remodelling mediated by TGF-β and attempt to integrate both processes in a broader picture.

Section snippets

TGF-β family members promote suppressive and repair responses

Cytokines of the TGF-β family are essential factors in embryonic development and tissue repair. This family includes, for example, three types of TGF-β (β1, β2 and β3), inhibins and activins, as well as various bone morphogenetic proteins (BMPs) and mullerian inhibiting substance. Activin βA and TGF-β1 share functions in inflammatory reactions including tissue repair and suppression 1., 2.. Both cytokines share SMAD2/3 and SMAD4 as intracellular signalling targets of their receptors [3]. The

Molecular basis of suppression and repair by TGF-β and activin βA

The signalling cascade induced by TGF-β is a very complex network (Figure 2), as several excellent reviews have described in great detail 3., 57., 58., 59., 60.. Although this complexity is disadvantageous to the design of well-controlled experiments, it does provide the opportunity to target selectively the functions of specific cell types. For example, our group has demonstrated that histamine and TGF-β synergize in the suppression of T cell proliferation by mechanism dependent on protein

Conclusions

In the past, TGF-β function was investigated under the focus of either tissue remodelling or immune regulation; however, a new generation of experiments in the field is considering TGF-β as a ‘recovery’ signal that incorporates both repair and regulation. The extensive work on the signalling pathways shows that TGF-β cannot convey these functions alone, but requires interactions with other signalling pathways at the ligand, receptor, second messenger and transcription factor level in order to

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by grants from the Swiss National Foundation (31-65436.01, 32-100266 and 3100A0-100164), by the Ehmann Foundation, the Saurer Foundation, the Jubiläumsstiftung der Schweizerischen Lebensversicherungs-und Rentenanstalt für Volksgesundheit und medizinische Forschung and the Ernst-Göhner Stiftung, Zug.

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