| First Author | Ishigame H | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 17 | Pages | 6961-6 |
| PubMed ID | 23569233 | Mgi Jnum | J:196160 |
| Mgi Id | MGI:5486616 | Doi | 10.1073/pnas.1304498110 |
| Citation | Ishigame H, et al. (2013) Excessive Th1 responses due to the absence of TGF-beta signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. Proc Natl Acad Sci U S A 110(17):6961-6 |
| abstractText | TGF-beta 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-beta signaling in Foxp3(+) regulatory T (Treg) cells contributes to immune homeostasis. Here we showed that abrogation of TGF-beta 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-gamma signaling alone completely suppressed diabetes development in these mice, indicating a critical role of Th1 cells in this model. Furthermore, deletion of TGF-beta 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-beta to suppress T1D. TGF-beta signaling was dispensable for Treg cell function, development, and maintenance, but excessive IFN-gamma production due to the absence of TGF-beta signaling in naive CD4(+) T cells indirectly caused dysregulated Treg cell homeostasis. We further showed that T cell-derived TGF-beta1 was critical for suppression of Th1 cell differentiation and T1D development. These results indicate that autocrine/paracrine TGF-beta signaling in diabetogenic CD4(+) T cells, but not Treg cells, is essential for controlling T1D development. |
