Reduced mTORC1 Signal in Autosomal Dominant Hyper-IgE Syndrome Can Be Partially Rescued with Addition of Exogenous Glutamine
Friday, June 24, 2022
3:05 PM – 3:20 PM PT
Location: Salons 5/6
Authors: Enrica Calzoni, n/a (Presenting Author) - Columbia University; Jacob Edinger, n/a (Co-Author) - Columbia University; Sarah Blackstone, n/a (Co-Author) - National Institute of Allergy and Infectious Diseases; Joshua Milner, n/a (Co-Author) - Columbia University
Senior Fellow Genentech South San Francisco, California, United States
Loss-of-function (LOF) mutations in the IL-6/STAT3 signaling pathway can lead to early life allergic inflammation, elevated IgE, and infection, though the mechanism for the allergic inflammation remains elusive, especially since IL-6 receptor blockade later in life does not lead to atopy. LOF mutations in the antigen receptor induced CARD11-BCL10-MALT1 complex can also lead to atopy, as well as impaired nuclear factor-kB and the mammalian target of rapamycin complex 1 (mTORC1) signaling. While NFkB component LOF does not lead to allergic disease in humans, mouse models strongly suggest that CARD11 and MALT1 are required for adequate mTORC1 activation via facilitating import of glutamine—leading to increased Treg function, increased Th1 and decreased Th2 differentiation. We therefore sought to determine if impaired mTORC1 signaling might also be observed and potentially underlie the atopy in a STAT3 dominant negative (DN) model. Here, we show that in mouse and in human T-cells, chemical inhibition or dominant negative mutations in STAT3 result in reduced TCR-induced mTORC1 signaling. The addition of exogenous glutamine could partially restore mTORC1 signaling in vitro. Allergic-inflammation associated RORgT-/T-bet+ Tregs—which can also result from dysbiosis—predominated in STAT3DN patients and mice, a phenotype which could also be reversed with glutamine supplementation. Finally, oral glutamine supplementation reduced total serum IgE levels in the STAT3DN mice. These data suggest that the STAT3 pathway is required for normal TCR-mediated mTORC1 signaling and prevention of allergic phenotypes early in life, and that exogenous glutamine can reverse some of the consequences of impaired STAT3 function.
