Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis

Abstract

The sustained immunosuppression associated with severe sepsis favors an increased susceptibility to secondary infections and remains incompletely understood. Plasmablast and plasma cell subsets, whose primary function is to secrete antibodies, have emerged as important suppressive populations that expand during sepsis. In particular, sepsis supports CD39hi plasmablast metabolic reprogramming associated with adenosine‐mediated suppressive activity. Arginine deficiency has been linked to an increased risk of secondary infections in sepsis. Overcoming arginine shortage by citrulline administration efficiently improves sepsis‐induced immunosuppression and secondary infections in the cecal ligation and puncture murine model. Here, we aimed to determine the impact of citrulline administration on B cell suppressive responses in sepsis. We demonstrate that restoring arginine bioavailability through citrulline administration markedly reduces the dominant extrafollicular B cell response, decreasing the immunosuppressive LAG3+ and CD39+ plasma cell populations, and restoring splenic follicles. At the molecular level, the IRF4/MYC‐mediated B cell reprogramming required for extrafollicular plasma cell differentiation is shunted in the splenic B cells of mice fed with citrulline. Our study reveals a prominent impact of nutrition on B cell responses and plasma cell differentiation and further supports the development of citrulline‐based clinical studies to prevent sepsis‐associated immune dysfunction.

Antagonist of CD39 and CD73 potentiate Doxycycline repositioning to induce potent antitumor immune response

“…4T1 or BMDM cells were seeded into a 96-well plate at a density of 10,000 cells per well in 10% FBS containing media. The cells were treated with doxycycline 20µg/ml, in the presence of the Real Time-Glo™ Extracellular ATP Assay Reagent (Promega, GA5010-1KT) [36].Luminescence data was collected every 6 hours using a BMG POLAR star® plate reader 2.11 Adenosine Assays: Adenosine was determined using culture supernatant of 4T1, BMDM and T cells samples by Adenosine Quanti cation Assay Kit (Sigma, MAK433-1KT) [37].According to the manufacturing recommendations, we have used 20µL of frozen plasma samples to measure adenosine concentration. The plate was read on spectraMaxM2 Spectro uorometer.…”