TGF-β receptor 3 (betaglycan) regulates Th1 differentiation and T dependent B cell responses.

Abstract

Abstract TGFβR3, also known as betaglycan, is a co-receptor for the TGFβ receptor and is predicted to have an important function in promoting high affinity binding of TGF-β to TGFβR1 or TGFβR2. TGFβR3 also binds inhibins with high affinity and antagonizes activin dependent activation of SMADs a function independent of TGFβR1/TGFβR2 signaling. Contrary to TGFβR1 and TGFβR2, our knowledge on the role of TGFβR3 in the immune system is very sparse. Its biology has been elusive because the knock-out of Tgfbr3 exhibit embryonic lethality. We developed the first Tgfbr3f/f mouse in which Cre mediated deletion of Tgfbr3 is very efficient. We found that deletion of TGFβR3 in thymic T cells (Tgfbr3f/f.CD4Cre) had no effect on CD4 or CD8 double positive (DP) or single positive (SP) T cell populations or peripheral T cell populations. Treg numbers in the thymus and periphery were unaltered and the mice did not develop spontaneous autoimmunity as observed when Tgfbr2 is deleted during thymic development. These observations indicated to us that TGFβR3 likely had a function independent of “classical” TGF-β signaling through TGFβR1/2 receptors. To test for this possibility we generated Tgfbr3f/f.dLckCre) mice in which is Tgfbr3 is selectively deleted in mature CD4 and CD8 T cells. We found that T dependent Ab responses, particularly of the IgG2c subclass, was greatly enhanced in mice with T-cell restricted loss of TGFβR3. We further determined that the differentiation of naïve CD4 T cells to IFN-γ expressing Th1 cells under polarizing and non-polarizing conditions was enhanced when TGFβR3 was deficient. These and other data indicate that regulation of Th1 differentiation by TGFβR3 is novel and independent of TGF-β signaling.