Sepsis expands a CD39+ plasmablast population that promotes immunosuppression via adenosine-mediated inhibition of macrophage antimicrobial activity

• DOI: 10.1016/j.immuni.2021.08.005
• Publication Date: 2021-09-01T14:30:26Z
• Authors: Daniele Carvalho ...; Paula Ramos Viacava; Raphael Gomes Fer...; Marina Alves Dama...; Annie Rocío Piñeros; Paulo Henrique Melo; Paula Barbim Donate; Juliana Escher To...; Daniel Zoppi; Flávio Protásio V...; Raphael Sanches P...; Luísa Menezes-Silva; Diego Caetité; Antonio Edson Roc...; Ícaro Maia Santos...; Gilles Kauffenstein; Helder Imoto Nakaya; Marcos Carvalho B...; Dario Simões Zamboni; Denise Morais Fon...; Jonas Augusto Riz...; Thiago Mattar Cunha; Valerie Quesniaux; Joel Linden; Fernando Queíroz ...; Bernhard Ryffel; José Carlos Alves...
• Keywords: Immunosuppression

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 CD39hi 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 CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease.