MICRORNA-10A NEGATIVELY REGULATES INTESTINAL IGA RESPONSE THROUGH SUPPRESSING REGULATORY T CELLS CONVERSION TO T FOLLICULAR REGULATOR CELLS

Abstract

Abstract Intestinal IgA response is a key immune regulation between host and gut microbiota. Regulatory T cells (Tregs) have been recently shown to promote IgA responses through conversion to T follicular regulator cells (TFRs). However, how Treg converts to TFR to promote intestinal IgA response remain unclear. Tregs express microRNA (miR)-10a at high levels, however, whether it regulates TFR generation and function is unknown. We found that Treg cell-specific miR-10a deficient Foxp3YFP-cre miR-10af/f (Foxp3ΔmiR-10a) mice displayed higher levels of gut IgA compared to wild type (WT) Foxp3YFP-cre miR-10af/+ mice. TFRs in Peyer’s patches were also significantly increased while there were no differences in germinal center B cells, Tregs, and TFH cells. When orally immunized with cholera toxin (CT), Foxp3ΔmiR-10a mice showed more CT-specific fecal IgA and TFRs. miR-10a deficient Tregs induced more IgA compared to WT Tregs when co-cultured with naïve B cells in vitro. When transferred to TCRβxδ−/− mice, miR-10a deficient Tregs induced more gut IgA and higher levels of TFRs compared to WT Tregs in vivo. However, gut microbiota composition in Foxp3ΔmiR-10a mice was not altered by 16S rRNA gene sequencing. RNA-sequencing analysis showed that miR-10a was enriched in the oxidative phosphorylation (OXPHOS) process in Tregs. Consistently, miR-10a deficient Tregs displayed higher OXPHOS metabolic levels by seahorse analysis. Pretreatment of Tregs with oligomycin, which inhibits OXPHOS, inhibited Treg induction of IgA production in vitro, indicating miR-10a suppressed Tregs induction of IgA ability by inhibiting OXPHOS. Thus, miR-10a negatively regulates TFRs conversion through inhibition of OXPHOS to control intestinal IgA response.