Purinergic regulation of adaptive immune system

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The importance of extracellular ATP for cell-to-cell communication in the nervous and vascular systems has been deeply studied for years, while less characterized is its role in regulating immune responses. Extracellular ATP is sensed by a class of ubiquitously expressed plasma membrane receptors termed P2 purinergic receptors (P2Rs), whose activation elicits different responses. Furthermore, extracellular ATP is rapidly degraded by ectonucleotidases such as CD39 and CD73 into adenosine, which in turn exerts additional regulatory effects through its own P1 receptors. In the first part of my PhD I addressed the role of ATP-gated ion channel P2X7 receptor in regulating T follicular helper (Tfh) cells functions. Tfh cells support affinity maturation of B cells in germinal centers (GCs) and differentiation to IgA-secreting plasma cells in gut-associated lymphoid tissues (GALTs). This function is critical in maintaining intestinal homeostasis and efficient mucosal defense. We have shown that P2X7 receptor is selectively and robustly upregulated in Tfh cells isolated from chronically stimulated secondary lymphoid organs, such as Peyer’s patches (PPs) and mesenteric lymph nodes. Deletion of P2rx7 in Tfh cells resulted in resistance to cell death, enhanced GC reaction in PPs, increased IgA binding to commensals, and reduction of mucosal bacteria. Our results unravel P2X7 as a regulator of the adaptive IgA response in the small intestine to allow commensalism and systemic stimulation of the immune system. In the second part of my PhD I addressed the role of the ectonucleotidases CD73 in the human B cell memory generation. It was previously shown from my host lab that peripheral human B cells co-expressing CD73 and CD39 have a more prompt capacity to expand and differentiate into antibody secreting cells in vitro. This property has been linked to the hydrolyzing enzymatic function of CD39 and CD73, which in tandem generates adenosine starting from extracellular ATP. We developed a method to functionally dissect antibody repertoire in different human B cell subsets differentiated according to CD73 expression and identified a novel subset of antigen-experienced B cells. We have shown for the first time that human peripheral IgM+IgD+CD27− B cells lacking expression of CD73 carry somatically mutated variable region genes, in contrast to CD73+ counterpart. Furthermore, IgM+IgD+CD27−CD73− B cells were less prone to perform class switch recombination in vitro and showed comparable functional properties with GC-independent memory B cells. Collectively, these results reveal CD73 as a novel human B cell marker that identifies functional distinct populations with different genetic hallmarks and a distinct differentiation fate.