Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation

Abstract

Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart, and brain. Alcohol also has strong immunoregulatory properties. Here, we report how alcohol impairs Tcell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. Tcells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces Tcell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescues the acetate-induced inhibition of Tcell migration, primary mouse cortactin knockout Tcells exhibited impaired migration. Acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in Tcells invitro and invivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of Tcell driven autoimmune diseases.