title: TGF-β signalling is required for CD4⁺ T cell homeostasis but dispensable for regulatory T cell function.
abstract: TGF-β is widely held to be critical for the maintenance and function of regulatory T (T(reg)) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-β receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-β-driven peripheral tolerance is not regulated by TGF-β signalling on mature CD4⁺ T cells. Inducible TR2 ablation specifically on CD4⁺ T cells did not result in a lethal autoinflammation. Transfer of these TR2-deficient CD4⁺ T cells to lymphopenic recipients resulted in colitis, but not overt autoimmunity. In contrast, thymic ablation of TR2 in combination with lymphopenia led to lethal multi-organ inflammation. Interestingly, deletion of TR2 on mature CD4⁺ T cells does not result in the collapse of the T(reg) cell population as observed in constitutive models. Instead, a pronounced enlargement of both regulatory and effector memory T cell pools was observed. This expansion is cell-intrinsic and seems to be caused by increased T cell receptor sensitivity independently of common gamma chain-dependent cytokine signals. The expression of Foxp3 and other regulatory T cells markers was not dependent on TGF-β signalling and the TR2-deficient T(reg) cells retained their suppressive function both in vitro and in vivo. In summary, absence of TGF-β signalling on mature CD4⁺ T cells is not responsible for breakdown of peripheral tolerance, but rather controls homeostasis of mature T cells in adult mice.
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Sledzińska
authors.forename: Saskia
authors.initials: S
authors.lastname: Hemmers
authors.forename: Florian
authors.initials: F
authors.lastname: Mair
authors.forename: Oliver
authors.initials: O
authors.lastname: Gorka
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Lynsey
authors.initials: L
authors.lastname: Fairbairn
authors.forename: Anja
authors.initials: A
authors.lastname: Nissler
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Thorsten
authors.initials: T
authors.lastname: Buch
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000473:pathology; D017353:Gene Deletion; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008231:Lymphopenia / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D013629:Tamoxifen / Q000494:pharmacology; D013950:Thymus Gland / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases