Regulation of T follicular helper cell response in Peyer’s patches by microbiota derived ATP via purinergic P2X7 receptor

Follicular B helper T (Tfh) cells in Peyer’s patches (PPs) promote B cells expansion, class switch recombination (CSR) and affinity IgA maturation. The anatomical location of PPs allows rapid mucosal amplification of B and T cell responses to small intestine endoluminal content. Adenosine triphosphate (ATP) is a ubiquitous extracellular messenger, which activates purinergic receptors in the plasma membrane termed P2 receptors. The P2X7 receptor subtype is an ATP-gated nonselective cationic channel expressed in a variety of cell types. In T cells protracted receptor stimulation leads to opening of a pore permeable to molecules up to 900 Da and cell death. We showed that P2X7 regulates Tfh cells abundance in PPs. Lack of P2X7 in Tfh cells enhanced the germinal centre reaction, high affinity IgA secretion and binding to commensals. The ensuing depletion of mucosal bacteria resulted in reduced systemic translocation of microbial components, which affected B1 cells stimulation and serum IgM levels. In the small intestine we detected ATP in the micromolar range; here we show that small intestine commensals release ATP that promotes PPs Tfh cell death via P2X7. Administration of bactericidal antibiotics per os resulted in ATP release by bacterial cell death that significantly impacted on Tfh cells number and endoluminal IgA concentration. Finally, we demonstrate that bacterially derived endoluminal ATP regulates T cell dependent IgA response and affect commensals abundance and composition.