TGF prevents IgE-mediated allergic disease by restraining T follicular helper 2 differentiation

Allergic diseases are common, affecting more than 20% of the population. Genetic variants in the TGF beta pathway are strongly associated with atopy. To interrogate the mechanisms underlying this association, we examined patients and mice with Loeys-Dietz syndrome (LDS) who harbor missense mutations in the kinase domain of TGF Beta R1/2. We demonstrate that LDS mutations lead to reduced TGF beta signaling and elevated total and allergen-specific IgE, despite the presence of wild-type T regulatory cells in a chimera model. Germinal center activity was enhanced in LDS and characterized by a selective increase in type 2 follicular helper T cells (T(FH)2). Expression of Pik3cg was increased in LDS T-FH cells and associated with reduced levels of the transcriptional repressor SnoN. PI3K gamma/mTOR signaling in LDS na & iuml;ve CD4(+) T cells was elevated after T cell receptor cross-linking, and pharmacologic inhibition of PI3K gamma or mTOR prevented exaggerated T(FH)2 and antigen-specific IgE responses after oral antigen exposure in an adoptive transfer model. Na & iuml;ve CD4(+) T cells from nonsyndromic allergic individuals also displayed decreased TGF beta signaling, suggesting that our mechanistic discoveries may be broadly relevant to allergic patients in general. Thus, TGF beta plays a conserved, T cell-intrinsic, and nonredundant role in restraining T(FH)2 development via the PI3K gamma/mTOR pathway and thereby protects against allergic disease.