| First Author | Haque TT | Year | 2024 |
| Journal | Sci Immunol | Volume | 9 |
| Issue | 91 | Pages | eadg8691 |
| PubMed ID | 38241399 | Mgi Jnum | J:362908 |
| Mgi Id | MGI:7782799 | Doi | 10.1126/sciimmunol.adg8691 |
| Citation | Haque TT, et al. (2024) TGFbeta prevents IgE-mediated allergic disease by restraining T follicular helper 2 differentiation. Sci Immunol 9(91):eadg8691 |
| abstractText | Allergic diseases are common, affecting more than 20% of the population. Genetic variants in the TGFbeta 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 TGFBetaR1/2. We demonstrate that LDS mutations lead to reduced TGFbeta 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. PI3Kgamma/mTOR signaling in LDS naive CD4(+) T cells was elevated after T cell receptor cross-linking, and pharmacologic inhibition of PI3Kgamma or mTOR prevented exaggerated T(FH)2 and antigen-specific IgE responses after oral antigen exposure in an adoptive transfer model. Naive CD4(+) T cells from nonsyndromic allergic individuals also displayed decreased TGFbeta signaling, suggesting that our mechanistic discoveries may be broadly relevant to allergic patients in general. Thus, TGFbeta plays a conserved, T cell-intrinsic, and nonredundant role in restraining T(FH)2 development via the PI3Kgamma/mTOR pathway and thereby protects against allergic disease. |
