Sepsis expands a CD39 plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity. Nascimento Daniele Carvalho,Viacava Paula Ramos,Ferreira Raphael Gomes,Damaceno Marina Alves,Piñeros Annie Rocío,Melo Paulo Henrique,Donate Paula Barbim,Toller-Kawahisa Juliana Escher,Zoppi Daniel,Veras Flávio Protásio,Peres Raphael Sanches,Menezes-Silva Luísa,Caetité Diego,Oliveira Antonio Edson Rocha,Castro Ícaro Maia Santos,Kauffenstein Gilles,Nakaya Helder Imoto,Borges Marcos Carvalho,Zamboni Dario Simões,Fonseca Denise Morais,Paschoal Jonas Augusto Rizzato,Cunha Thiago Mattar,Quesniaux Valerie,Linden Joel,Cunha Fernando Queíroz,Ryffel Bernhard,Alves-Filho José Carlos Immunity Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39 B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39 plasmablasts and adenosine accumulation. Our study reveals CD39 plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease. 10.1016/j.immuni.2021.08.005