| Title: |
TGFβ prevents IgE-mediated allergic disease by restraining T follicular helper 2 differentiation. |
| Authors: |
Haque, Tamara T.; Weissler, Katherine A.; Schmiechen, Zoe; Laky, Karen; Schwartz, Daniella M.; Li, Jenny; Locci, Michela; Turfkruyer, Mathilde; Yao, Chen; Schaughency, Paul; Leak, Lashawna; Lack, Justin; Kanno, Yuka; O'Shea, John; Frischmeyer-Guerrerio, Pamela A. |
| Source: |
Science Immunology; 2024, Vol. 9 Issue 91, p1-15, 15p |
| Subject Terms: |
Allergies; T helper cells; Regulatory T cells; Atopy; T cell receptors; T cells |
| 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 (TFH2). Expression of Pik3cg was increased in LDS TFH 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 TFH2 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 TFH2 development via the PI3Kγ/mTOR pathway and thereby protects against allergic disease. Editor's summary: The production of IgE antibodies is a hallmark of allergy, and variants in the TGFβ pathway are associated with atopic conditions. To determine how TGFβ signaling regulates IgE production in allergic disease, Haque et al. studied Loeys-Dietz syndrome (LDS) patients and mice with a single gene defect leading to partially attenuated canonical TGFβ signaling. CD4+ T cells from LDS patients and mice had impaired TGFβ signaling, which correlated with atopy. LDS mutations resulted in increased T follicular helper 2 cells, exaggerated humoral immune responses and production of allergen specific IgE. LDS variants resulted in dysregulated PI3Kγ/mTOR signaling, and this was rescued by pharmacological inhibition. Together these findings identify TGFβ as an essential regulator of Tfh2 differentiation through the PI3Kγ/mTOR pathway in T cells. — Hannah Isles [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |