The effects of altered TGFβ signaling on human T follicular helper cell development and function

Abstract

Abstract T follicular helper (Tfh) cells are a subset of CD4+ T cells that play a crucial role in the development of memory B cells and plasma cells. T follicular regulatory (Tfr) cells oppose Tfh cells and suppress humoral immune responses. Patients with Loeys-Dietz Syndrome (LDS) type 1 and 2 have an autosomal dominant mutation in the genes encoding TGFβ Receptor 1 or 2, respectively, and have a strong predisposition to develop allergic diseases. We hypothesized that altered development and function of Tfh cells could contribute to increased IgE-mediated allergic phenotypes in LDS. Comparing a cohort of pediatric LDS patients with age-matched healthy volunteers, we found that LDS patients have significantly higher levels of serum IgE and IgG and lower levels of IgM. Congruently, LDS patients have an increased frequency of memory T cells, Th2 cells, and Tfh cells and a significantly lower frequency of Tfr cells. The increase in Tfh cells in LDS was restricted to the CCR4+ CCR6− subset, which has been associated with Th2 immune responses. In vitro, Tfh cells from LDS patients co-cultured with autologous naïve B cells demonstrated a greater ability to induce plasma cell differentiation compared to age-matched healthy volunteers. Additionally, naïve CD4+ T cells from LDS patients cultured in the presence of recombinant TGFβ1 and IL-12 or IL-4 were more likely to differentiate into Tfh cells compared to healthy age-matched controls, suggesting a cell-intrinsic propensity for naïve CD4+ T cells in LDS patients to acquire a Tfh fate. Collectively, our data suggest that LDS mutations alter the development and function of Tfh cells in a manner that promotes IgE-mediated disease.