PD-1 blockade promotes mucosal CD4+ T cell IL-10 production through altering microbiota to reduce intestinal ischemia...

PD-1 blockade therapy is widely used in clinical practice. Intestinal ischemia reperfusion (IR) injury is a serious clinical complication that leads to remote organ damage through disruption of the gut barrier. However, the effects of PD-1 blockade on gut homeostasis and intestinal IR injury remain unclear. Here, we demonstrate that, in contrast to PD-1 deficiency, PD-1 blockade activates intestinal immunoglobulin A (IgA) responses in mice via a MyD88-dependent pathway. The increased production and bacteria-binding capacity of IgA induced by PD-1 blockade significantly reshape the gut microbial composition and metabolite profile. Furthermore, PD-1 blockade promotes intestinal mucosal CD4+ T cell IL-10 production. Notably, microbiota depletion by antibiotics attenuates intestinal IL-10 production, whereas transplantation of PD-1 blockade-altered microbiota facilitates IL-10 upregulation. These IL-10 enhancements appears to be driven by an increase in Lachnospiraceae_NK4A136_group, a recognized butyrate-producing bacterium, and elevated levels of microbiota-derived butyrate, which were increased after PD-1 blockade and significantly correlated with enhanced IL-10 production in the intestinal mucosa. The upregulation of intestinal IL-10 following PD-1 blockade suppresses inflammatory activation, thereby ameliorating the gut barrier impairment and remote organ injury induced by intestinal IR. In addition, we show that, in vivo and in vitro, butyrate supplementation enhances IL-10 expression in CD4+ T cells through PI3Kγ/phospho-mTOR signaling. Collectively, these findings indicate that PD-1 blockade promotes intestinal mucosal CD4+ T cell IL-10 production by modulating immune‒microbiota interactions and subsequently mitigates intestinal IR-induced gut barrier dysfunction and organ damage.