Prostaglandin I2 signaling restrains IL-13+ T follicular helper cell formation and IgE generation in allergic airway inflammation 2421

Description Prostaglandin I2 (PGI2) signaling suppresses the function of T helper type 2 (Th2) and group 2 innate lymphoid (ILC2) cells in allergic airway inflammation (AAI). T follicular helper (Tfh) cells promote the development of AAI by promoting isotype switching within B cells to IgE and increasing antibody production. Studies have reported an IL-13+ Tfh subset that promotes the formation of high-affinity IgE in allergy. PGI2 signaling restrains IL-13 production from Th2 and ILC2. Thus, we hypothesized that PGI2 signaling limits the generation of IL-13+ Tfh, and thereby IgE production. To test this hypothesis, we challenged WT and mice globally deficient in the PGI2 receptor IP (IP KO) with Alternaria alternata (Alt) extract every 3 days for 4 challenges and then harvested the mice 1 day after the last challenge. We found that IP KO mice had increased total numbers of IL-13+ Tfh cells in their mediastinal lymph nodes (LN), and increased serum and lung IgE compared to WT mice. Next, we generated Bcl6tdtomatocreERT2xIPflox mice. Bcl6 is the master transcription factor for Tfh cells and is also important for germinal center (GC) B cell function, therefore these mice have no PGI2 signaling in their GCs. We found that Bcl6tdtomatocreERT2xIPflox mice have significantly more total LN IL-13+ Tfh cells and GC B cells, and serum IgE and lung IgE, than Bcl6tdtomatocreERT2 mice after Alt challenge. Thus, PGI2 signaling restrains IL-13+ Tfh formation and downstream GC IgE production in AAI. Funding Sources Supported by Showatler Trust Indiana CTSI; NIH K99/R00HL159-594; NIH R01AI145265 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)