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TregGF-β: Deletion of TGF-β in Tregs revisited

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Science Immunology  05 Feb 2021:
Vol. 6, Issue 56, eabg7284
DOI: 10.1126/sciimmunol.abg7284

Abstract

Treg-specific ablation of TGF-β clarifies the complicated role of Treg-derived TGF-β in immunosuppression in vivo.

Regulatory T cells (Tregs) use multiple suppressive mechanisms to enforce immune tolerance in different biological contexts. The cytokine TGF-β was initially identified as a Treg suppressive mechanism over two decades ago. Because TGF-β has pleiotropic effects that may vary depending on the biological context and the precise cell types involved, formal demonstration that Treg-derived TGF-β is required for immune homeostasis in vivo is crucial to understanding the role of this cytokine in immune regulation. However, this has proved elusive. The complex biology of TGF-β has confounded many genetic and pharmacologic studies, because it can be produced, activated, and sensed by numerous cell types. Additionally, early conditional knockout mouse strains affected the nearby B9d2 gene, necessitating complex genetic strategies for cell type–specific deletion and generating conflicting data on the necessity of Treg-derived TGF-β for immune suppression.

Turner et al. revisit the issue with a variety of genetic tools, including two Treg-specific Cre drivers, an updated Tgfb1-flox allele, and a cell type–specific TGF-β overexpressing strain.3 They find that haploinsufficiency of TGF-β in Tregs results in increased sensitivity to food allergy associated with a reduction in intestinal RORγt+ Tregs, a microbiota-induced Treg subset that suppresses TH2 responses. Subsequent experiments demonstrate that gut colonization with Clostridiales bacteria stimulates TGF-β from Tregs, while signaling through IL-4R reduces Treg TGF-β production. The authors then find that signaling through the TGF-β receptor on Tregs is necessary for RORγt+ Treg accumulation and suppression of food allergy and suggest that Treg-derived TGF-β may promote RORγt+ Treg differentiation in an autocrine fashion. Finally, biallelic loss of TGF-β in Tregs causes a surprisingly profound autoimmune syndrome that mimics scurfy mice, which lack Tregs altogether.

These results clearly demonstrate that Treg secretion of TGF-β is crucial to in vivo immunosuppression. However, questions remain: For instance, because TGF-β is necessary for normal Treg development, it is difficult to distinguish direct suppressive effects of TGF-β from alterations in Treg development with the authors’ experimental systems, in which TGF-β is constitutively deleted from all Tregs. Further work may therefore help untangle additional mechanistic details of this complex pathway.

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