title: Excessive Th1 responses due to the absence of TGF-β signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis.
abstract: TGF-β signaling in T cells is critical for peripheral T-cell tolerance by regulating effector CD4(+) T helper (Th) cell differentiation. However, it is still controversial to what extent TGF-β signaling in Foxp3(+) regulatory T (Treg) cells contributes to immune homeostasis. Here we showed that abrogation of TGF-β signaling in thymic T cells led to rapid type 1 diabetes (T1D) development in NOD mice transgenic for the BDC2.5 T-cell receptor. Disease development in these mice was associated with increased peripheral Th1 cells, whereas Th17 cells and Foxp3(+) Treg cells were reduced. Blocking of IFN-γ signaling alone completely suppressed diabetes development in these mice, indicating a critical role of Th1 cells in this model. Furthermore, deletion of TGF-β signaling in peripheral effector CD4(+) T cells, but not Treg cells, also resulted in rapid T1D development, suggesting that conventional CD4(+) T cells are the main targets of TGF-β to suppress T1D. TGF-β signaling was dispensable for Treg cell function, development, and maintenance, but excessive IFN-γ production due to the absence of TGF-β signaling in naive CD4(+) T cells indirectly caused dysregulated Treg cell homeostasis. We further showed that T cell-derived TGF-β1 was critical for suppression of Th1 cell differentiation and T1D development. These results indicate that autocrine/paracrine TGF-β signaling in diabetogenic CD4(+) T cells, but not Treg cells, is essential for controlling T1D development.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Harumichi
authors.initials: H
authors.lastname: Ishigame
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Zenewicz
authors.forename: Shomyseh
authors.initials: S
authors.lastname: Sanjabi
authors.forename: Paula
authors.initials: P
authors.lastname: Licona-Limón
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology; D005434:Flow Cytometry; D006706:Homeostasis / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D017931:DNA Primers; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma