Dependence of Immunoglobulin Class Switch Recombination in B Cells on Vesicular Release of ATP and CD73 Ectonucleotidase Activity

• Published in: Cell reports (Cambridge) Vol. 3; no. 6; pp. 1824 - 1831
• Main Authors: Schena, Francesca, Volpi, Stefano, Faliti, Caterina Elisa, Penco, Federica, Santi, Spartaco, Proietti, Michele, Schenk, Ursula, Damonte, Gianluca, Salis, Annalisa, Bellotti, Marta, Fais, Franco, Tenca, Claudya, Gattorno, Marco, Eibel, Hermann, Rizzi, Marta, Warnatz, Klaus, Idzko, Marco, Ayata, Cemil Korcan, Rakhmanov, Mirzokhid, Galli, Thierry, Martini, Alberto, Canossa, Marco, Grassi, Fabio, Traggiai, Elisabetta
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2013; Elsevier
• Subjects: 5'-Nucleotidase - genetics; 5'-Nucleotidase - immunology; 5'-Nucleotidase - metabolism; Adenosine Triphosphate - genetics; Adenosine Triphosphate - immunology; Adenosine Triphosphate - metabolism; Animals; Antibody Formation - genetics; Antibody Formation - immunology; Antigens, CD - immunology; Antigens, CD - metabolism; Apyrase - immunology; Apyrase - metabolism; B-Lymphocyte Subsets - cytology; B-Lymphocyte Subsets - immunology; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Common Variable Immunodeficiency - metabolism; Humans; Immunoglobulin Class Switching - immunology; Mice; Mice, Transgenic; Recombination, Genetic
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.05.022

Immunoglobulin (Ig) isotype diversification by class switch recombination (CSR) is an essential process for mounting a protective humoral immune response. Ig CSR deficiencies in humans can result from an intrinsic B cell defect; however, most of these deficiencies are still molecularly undefined and diagnosed as common variable immunodeficiency (CVID). Here, we show that extracellular adenosine critically contributes to CSR in human naive and IgM memory B cells. In these cells, coordinate stimulation of B cell receptor and toll-like receptors results in the release of ATP stored in Ca2+-sensitive secretory vesicles. Plasma membrane ectonucleoside triphosphate diphosphohydrolase 1 CD39 and ecto-5′-nucleotidase CD73 hydrolyze ATP to adenosine, which induces CSR in B cells in an autonomous fashion. Notably, CVID patients with impaired class-switched antibody responses are selectively deficient in CD73 expression in B cells, suggesting that CD73-dependent adenosine generation contributes to the pathogenesis of this disease. [Display omitted] •In B cells, ATP is stored in secretory vesicles•B cell activation induces ATP release•Adenosine generated by CD39 and CD73 in B cells promotes class switch recombination•Patients with common variable immunodeficiency are selectively deficient in CD73 Extracellular nucleotides regulate diverse cellular functions through purinergic receptors. Whether purinergic signaling regulates B cell physiology is largely unknown. Traggiai and colleagues now report that activated B cells release ATP stored in secretory vesicles. ATP is hydrolyzed by the combined activity of plasma membrane ectonucleotidases CD39/ENTPD1 and CD73/NT5E to adenosine, which promotes immunoglobulin class switch recombination. A subset of patients with common variable immunodeficiency with hypogammaglobulinemia display reduced CD73 activity, suggesting that impaired generation of adenosine may contribute to hypogammaglobulinemia.