Excessive Th1 responses due to the absence of TGF-? signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis.

ABSTRACT: TGF-? 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-? signaling in Foxp3(+) regulatory T (Treg) cells contributes to immune homeostasis. Here we showed that abrogation of TGF-? 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-? signaling alone completely suppressed diabetes development in these mice, indicating a critical role of Th1 cells in this model. Furthermore, deletion of TGF-? 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-? to suppress T1D. TGF-? signaling was dispensable for Treg cell function, development, and maintenance, but excessive IFN-? production due to the absence of TGF-? signaling in naive CD4(+) T cells indirectly caused dysregulated Treg cell homeostasis. We further showed that T cell-derived TGF-?1 was critical for suppression of Th1 cell differentiation and T1D development. These results indicate that autocrine/paracrine TGF-? signaling in diabetogenic CD4(+) T cells, but not Treg cells, is essential for controlling T1D development.

SUBMITTER: Ishigame H 

PROVIDER: S-EPMC3637710 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature