Dysregulated TGF-β Signaling Leads to Cell-Intrinsic Changes in T cell Development that Promote Allergic Inflammation

Abstract

Abstract Variants in genes in the Transforming Growth Factor Beta (TGFβ) signaling pathway are associated with allergic diseases suggesting that this cytokine may be a central player in the allergic diathesis. The role of TGFβ in preserving T cell mediated self-tolerance is well appreciated but how disruption in this pathway promotes allergic inflammation is unclear. We previously demonstrated that patients with Loeys-Dietz Syndrome (LDS), an autosomal dominant disorder caused by mutations in TGFBR1 and TGFBR2, are highly predisposed to allergic disease. LDS patients and mice harboring a knock in allele (Tgfbr1mut) of an LDS mutation known to cause severe disease in humans exhibit higher levels of total and food specific IgE. These serologic changes were associated with higher frequencies of T follicular helper (Tfh) cells and lower T follicular regulatory (Tfr) cells. Using a mixed bone marrow and fetal liver chimera model, we showed that these alterations in T cell development are cell intrinsic. Chimera models also demonstrated that the TGFβ mutation drives higher IgE production despite the presence of wildtype Tregs. Furthermore OVA specific Tgfbr1mutOTII cells were more likely to accumulate in the peyers patch and differentiate into Tfh cells in response to orally ingested OVA. These findings correlated with increased AKT/pS6 signaling downstream of TCR in Tgfbr1mut T cells, and mTOR inhibition decreased Tgfbr1mut OTII Tfh cells in response to fed ova. Additionally, RNA sequence analysis of murine Tgfbr1mut Tfh cells revealed enhanced PI3K/AKT pathway activity. These findings suggest that TGFβ signaling plays an important role in T cell development and function via the PI3K/AKT pathway that when disrupted promotes allergic inflammation.