Importance of TGF-beta Signaling in Dendritic Cells to Maintain Immune Tolerance

Abstract

TGFβ is an immunoregulatory cytokine that has a pivotal function in maintenance of immune tolerance via the control of lymphocyte proliferation, differentiation and survival. Defects in TGFβ1 expression or in its signaling in T cells correlate with the onset of several autoimmune diseases. However, the early effects of this cytokine on the innate immune system, particularly the dendritic cells (DCs) which play an equally important role in development of immune tolerance, are not well documented in vivo. In the current study, we developed conditional knockout mice with targeted deletion of Tgfbr2 specifically in dendritic cells. DC-Tgfbr2 KO mice developed spontaneous multi-organ autoimmune inflammation with T and B cell activation. Phenotypic analysis of dendritic cells revealed no significant differences in the expression of MHCII and co-stimulatory molecules between control and DC-Tgfbr2 KO mice. However, we found that DCs from DC-Tgfbr2 KO mice were more pro-inflammatory, which exacerbated the severity of disease in a T cell transfer model of colitis. Furthermore, increased IFNγ expression by Tgfbr2-deficient DCs inhibited antigen-specific regulatory T cells (Tregs) differentiation by DCs in the presence of TGFβ. Since DCs play an important role in Treg homeostasis in vivo, we also examined the phenotype of Tregs and observed a significant increase in the frequency and numbers of Foxp3⁺ T cells in both the spleen and MLNs of DC- Tgfbr2 KO mice. Further analysis of these Tregs revealed attenuated expression of Foxp3 and an expansion in the numbers of CD4⁺CD25⁻Foxp3⁺T cells suggesting that the Tregs from KO mice may not be fully immunosuppressive. Adoptive transfer of in vitro differentiated iTregs into 2-3 week old DC-Tgfbr2 KO mice partially rescued the autoimmune phenotype by reducing the frequency of activated T cells and severity of colitis but did not prevent inflammation in other organs. The phenotype of this novel mouse model clearly indicates the importance of TGFβ signaling in DCs in the maintenance of immune homeostasis and prevention of autoimmunity and provides an opportunity to study the pathogenesis of complex disorders such as autoimmune gastritis, pancreatitis, hepatitis and inflammatory bowel diseases.