Adenosine 2A receptor antagonists promote lymphocyte proliferation in sepsis by inhibiting Treg expression of PD‐L1 in spleen

Abstract The spleen is essential for lymphocyte proliferation, which is associated to sepsis prognosis. Adenosine 2A receptor (A2AR) blocking promotes lymphocyte proliferation in sepsis, however the mechanism is uncertain. Our sepsis cecum ligation perforation model showed that blocking A2AR increased survival and CD4+ cell numbers in a spleen‐dependent mechanism. The sequencing of the transcriptome of the spleen indicated alterations in the expression of genes involved in the control of lymphocyte proliferation by inhibiting A2AR, including a reduction in the expression of PD‐L1. Flow cytometry analysis of PD‐L1 expression intensity in splenic cell subpopulations revealed that the Treg cell subpopulation was the strongest PD‐L1‐expressing cell population, and Treg PD‐L1 expression decreased after blocking A2AR. In vitro activation of A2AR was able to upregulate PD‐L1 expression of Treg and boost Treg capacity to limit lymphocyte proliferation, while blockage of PD‐L1 partly reduced A2AR‐activated Treg's ability to inhibit lymphocyte proliferation. In addition, blocking CREB phosphorylation significantly inhibited A2AR‐induced PD‐L1 expression. According to the findings of our research, inhibiting A2AR improves the prognosis of sepsis by lowering the level of PD‐L1 expression by Treg in the spleen and reducing the inhibition of lymphocyte proliferation.