TGFβ prevents IgE-mediated allergic disease by restraining T follicular helper 2 differentiation
Tamara T. Haque, Katherine A. Weissler, Zoe C. Schmiechen, Karen Laky, Daniella M. Schwartz, Jenny Li, Michela Locci, Mathilde Turfkruyer, Chen Yao, Paul Schaughency, Lashawna Leak, Justin Lack, Yuka Kanno, John J. O’Shea, Pamela A. Frischmeyer‐Guerrerio
Abstract
Allergic diseases are common, affecting more than 20% of the population. Genetic variants in the TGFβ 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 TGFΒR1/2 . We demonstrate that LDS mutations lead to reduced TGFβ 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. PI3Kγ/mTOR signaling in LDS naïve CD4 + T cells was elevated after T cell receptor cross-linking, and pharmacologic inhibition of PI3Kγ or mTOR prevented exaggerated T FH 2 and antigen-specific IgE responses after oral antigen exposure in an adoptive transfer model. Naïve CD4 + T cells from nonsyndromic allergic individuals also displayed decreased TGFβ signaling, suggesting that our mechanistic discoveries may be broadly relevant to allergic patients in general. Thus, TGFβ plays a conserved, T cell–intrinsic, and nonredundant role in restraining T FH 2 development via the PI3Kγ/mTOR pathway and thereby protects against allergic disease.