TGFβ Receptor Mutations Impose a Strong Predisposition for Human Allergic Disease

Transforming growth factor-beta (TGF beta) is a multifunctional cytokine that plays diverse roles in physiologic processes as well as human disease, including cancer, heart disease, and fibrotic disorders. In the immune system, TGF beta regulates regulatory T cell (T-reg) maturation and immune homeostasis. Although genetic manipulation of the TGF beta pathway modulates immune tolerance in mouse models, the contribution of this pathway to human allergic phenotypes is not well understood. We demonstrate that patients with Loeys-Dietz syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding receptor subunits for TGF beta, TGFBR1 and TGFBR2, are strongly predisposed to develop allergic disease, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. LDS patients exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (T(H)2) cytokines in their plasma. They had an increased frequency of CD4(+) T cells that expressed both Foxp3 and interleukin-13, but retained the ability to suppress effector T cell proliferation. T(H)2 cytokine-producing cells accumulated in cultures of naive CD4(+) T cells from LDS subjects, but not controls, after stimulation with TGF beta, suggesting that LDS mutations support T(H)2 skewing in naive lymphocytes in a cell-autonomous manner. The monogenic nature of LDS demonstrates that altered TGF beta signaling can predispose to allergic phenotypes in humans and underscores a prominent role for TGF beta in directing immune responses to antigens present in the environment and foods. This paradigm may be relevant to nonsyndromic presentations of allergic disease and highlights the potential therapeutic benefit of strategies that inhibit TGF beta signaling.