TFR cell-mediated regulation of IgA and gut microbiota in food allergy

Abstract

Abstract About two grams of secretory Immunoglobulin A (sIgA) are secreted daily into the intestine, where it serves as the first line of defense against pathogens and protects the host's commensals by coating them, ensuring mucosal immune system homeostasis. Gut microbiota (Mb)-specific IgA can be generated via T cell-dependent (TD) or T cell-independent (TI) pathways. However, the TD route is required to generate high-affinity, pathogen-specific antibodies (Abs). T follicular helper (Tfh) cells are essential for germinal center (GC) development, promoting B cells expansion. Nevertheless, the role of T follicular regulatory (Tfr) cells in Mb-reactive IgA production is unclear. Unpublished results and a prior work demonstrated that deleting Tregs or Tfr cells in mice increased antigen-specific IgA titers, indicating that these cells negatively control IgA response. Thus, we hypothesized that TFR cells regulate gut Mb-reactive IgA via the regulation of high-affinity IgA production against gut Mb. To test this hypothesis, TFR cell-deficient Bcl6FC (Foxp3 cre-Bcl6 fl/fl) and WT mice were primed with peanut plus cholera toxin through oral gavage in a food allergy model. Then, we stained fecal Mb with anti-mouse IgA, sorted commensals into IgA +and IgA −populations and sequence 16S rRNA gene of the sorted bacteria (IgA-seq) to evaluate the Mb-reactive IgA response. Flow cytometry data showed significantly higher IgA-coated bacteria in Bcl6FC than in WT mice, showing TFR cells adversely modulate IgA response to gut Mb. Our current experiments will dissect if the higher Mb-reactive IgA secreted in the absence of TFR cells were non-specific and polyreactive or were specific towards certain members of gut commensals. R21 AI172087 NIH