Figure 2.

Lactate regulates lymphocyte function. (A) Lactate regulates CD4⁺ T cell function by the following mechanisms: inhibiting glycolysis and thus migration, disrupting the balance between NAD⁺ and NADH, mediating an increase in STAT3 phosphorylation by affecting PKM2 nuclear translocation and facilitating fatty acid synthesis, thereby increasing IL-17 production, and regulating gene expression by lactylation of Ikzf1, which facilitates differentiation to Th17 cells. (B) Lactate modulates CD8⁺ T cells by mechanisms such as, inhibiting glycolysis and thus migration, disrupting the balance between NAD⁺ and NADH, affecting pyruvate metabolism and thus reducing cytotoxicity, inhibiting histone deacetylase (HDAC) and thus promoting acetylation of histone H3K27 and thus increasing anti-tumor immunity, and its inhibition of the glycolytic enzyme GAPDH contributes to the production of IFN-γ, but appears to inhibit TCR-mediated IFN-γ production. (C) For Treg cells, in addition to limiting glycolysis, lactate binding to GPR81 enhances their infiltrative capacity, it improves PD1 expression by increasing the NAFT1 nuclear translocation mechanism, and it mediates high CTLA4 expression by up-regulating Foxp3, and lactate also promotes the lactylation of MOESIN to improve Treg function. (D) Lactate acts on B cells by the following mechanisms: promotion of germinal center function, inhibition of glycolysis, promotion of proliferation through increased ANG expression or positive feedback through miR-223-mediated lactate production, and lactate mediates the acetylation of histone H3K27 and thus promotes IgG class switching. Red colored arrows indicate activated events, while blue colored arrows indicate suppressed events, by lactate during sepsis/septic shock.