Deficiency of H3K27 histone demethylase UTX in T cells blunts allergic sensitization and anaphylaxis to peanut.

Abstract

Whether epigenetic factor UTX, a histone H3 lysine 27 (H3K27) demethylase, is critical for type 2 immunity, including allergic sensitization and antigen-driven anaphylaxis, is unclear. We used UTXfl/fl x Lck-Cre mice with UTX-deficient T cells (UTX-TCD) to determine whether T cell-specific UTX expression regulates antigen-specific IgE production after airway sensitization to peanut and anaphylaxis following intraperitoneal (i.p.) peanut challenge. UTX-TCD mice sensitized via the airway with peanut and lipopolysaccharide (LPS), a bacterial component and environmental adjuvant found in house dust, made 2-fold less peanut-IgE and 3.5-fold less peanut-IgG1 than comparably sensitized UTXfl/fl mice, despite higher total IgE and total IgG1 serum antibody levels pre-sensitization. Peanut-induced anaphylaxis was blunted in UTX-TCD mice, with maximum drop in core body temperature after i.p. peanut challenge two-fold lower than in UTXfl/fl mice. Compared to UTXfl/fl controls, UTX-TCD mice had reduced frequencies of CD4+ T-follicular helper (Tfh) cells and germinal center B cells, but higher frequencies of IL-4+ T-helper (Th)2, Tfh2, and IL-13+ Tfh13 cells in airway-draining mediastinal lymph nodes. UTX-TCD mice also skewed toward type 2 antibody and T-helper immune responses independent of allergic sensitization, with fewer IL-10-producing splenic Treg and T-follicular regulatory (Tfr) cells. Our results suggest that UTX expression in T cells impact the production of antigen-specific antibody responses required for allergic sensitization and antigen-specific allergic reactions, suggesting a role for H3K27 histone demethylase UTX in regulating type 2 immunity.