T cell restricted TGF-βR3 (betaglycan) null mice develop exacerbated experimental autoimmune encephalomyelitis (EAE) associated with expanded generation of Th1 cells

Abstract

TGF-β receptor 3 (TGFβ-R3), also known as betaglycan, promotes high-affinity binding of TGF-β (1, 2 and 3) to TGFβ-R1 and TGFβ-R2 and is also a receptor for bone morphogenetic proteins (BMP) and inhibins. The embryonic lethality of TGFβ-R3 knock-outs hindered the understanding of its mechanistic function in immune response. To interrogate the function of TGFβ-R3 in mature T cells (T-Tgfbr3KO), we generated a conditional Tgfbr3f/f mouse and bred it with the dLckCre mouse. We found EAE in mice with T-Tgfbr3KO developed with greater severity and mortality than WT littermate mice in both males and females. The onset of disease was similar. The greater severity in T cell T-Tgfbr3KO mice was associated with increased proportion of Th1 cells in the CNS with no difference in numbers of Th17 cells. OT2 T-Tgfbr3KO CD4 T cells also polarized more efficiently to Th1 cells than T-Tgfbr3WT CD4 T cells. The lack of TGF-βR3 had no significant effect on differentiation of Th17 cells. Since our results indicates that TGF-βR3 regulates differentiation to IFN-γ expressing T cells, we interrogated if T-dependent B cells responses to IFN-γ switching will be altered in mice immunized with TNP-KLH. We found that IFN-γ switch dependent anti-TNP IgG2c and IgG3 was greatly enhanced in T-Tgfbr3KO mice compared to WT littermates. All other isotypes were similar in both groups. Our data reveal a novel role for TGFβ-R3 in regulating differentiation of naïve CD4 T cells to IFN-γ expressing cells.

Transforming Growth Factor Beta Receptor 3 (TGFBR3)–Associated Membranous Nephropathy

“…TGFBR3 has been shown to be protective against autoimmunity, reducing T cell–dependent antibody responses with reduced differentiation of CD4 + T cells to proinflammatory T-helper 1 cells, the latter of which secrete IFN- γ (19), a cytokine implicated in multiple autoimmune diseases, including SLE. Absence of TGFBR3 exacerbates experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, demonstrating protection of TGFBR3 in autoimmunity (20). We have identified TGFBR3 as a biomarker of a novel subtype of MN.…”