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Inflammatory and anti-inflammatory cytokines play an important role in the generation of effector and memory CD8(+) T cells. We used two different models, transgenic expression of truncated (dominant negative) form of TGF-βRII (dnTGFβRII) and Cre-mediated deletion of the floxed TGF-βRII to examine the role of TGF-β signaling in the formation, function, and homeostatic proliferation of memory CD8(+) T cells. Blocking TGF-β signaling in effector CD8(+) T cells using both of these models demonstrated a role for TGF-β in regulating the number of short-lived effector cells but did not alter memory CD8(+) T cell formation and their function upon Listeria monocytogenes infection in mice. Interestingly, however, a massive lymphoproliferative disorder and cellular transformation were observed in Ag-experienced and homeostatically generated memory CD8(+) T cells only in cells that express the dnTGFβRII and not in cells with a complete deletion of TGF-βRII. Furthermore, the development of transformed memory CD8(+) T cells expressing dnTGFβRII was IL-7- and IL-15-independent, and MHC class I was not required for their proliferation. We show that transgenic expression of the dnTGFβRII, rather than the absence of TGF-βRII-mediated signaling, is responsible for dysregulated expansion of memory CD8(+) T cells. This study uncovers a previously unrecognized dominant function of the dnTGFβRII in CD8(+) T cell proliferation and cellular transformation, which is caused by a mechanism that is different from the absence of TGF-β signaling. These results should be considered during both basic and translational studies where there is a desire to block TGF-β signaling in CD8(+) T cells.

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.

IL-1 receptor antagonist (IL-1Ra)-deficient mice spontaneously develop several inflammatory diseases, resembling rheumatoid arthritis, aortitis, and psoriasis in humans. As adoptive T cell transplantation could induce arthritis and aortitis in recipient mice, it was suggested that an autoimmune process is involved in the development of diseases. In contrast, as dermatitis developed in scid/scid-IL-IRa-deficient mice and could not be induced by T cell transfer, a T cell-independent mechanism was suggested. The expression of proinflammatory cytokines was augmented at the inflammatory sites. The development of arthritis and aortitis was significantly suppressed by the deficiency of TNFalpha or IL-17. The development of dermatitis was also inhibited by the deficiency of TNFalpha. These observations suggest that TNFalpha and IL-17 play a crucial role in the development of autoimmunity downstream of IL-1 signaling, and excess IL-1 signaling-induced TNFalpha also induces skin inflammation in a T cell-independent manner.