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

Summary 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 T cell 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. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces T cell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescued the acetate-induced inhibition of T cell migration, primary mouse cortactin knock-out T cells exhibited impaired migration. Furthermore, acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells in vitro and in vivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of T cell driven autoimmune diseases.