Excessive alcohol consumption inhibits a variety of immunological functions and decreases resistance to several infectious agents, notably HIV and HCV. This increased susceptibility to infection is believed to be mediated by a dysregulation of both the innate and adaptive arms of the immune system. T cells play a critical role in combatting viral infections and several studies have examined the impact of ethanol on T cell responses during infection. However, given that pathogens can interfere with the immune response, it remains critical to understand the impact of ethanol alone on T cell homeostasis. This type of analysis can reveal the mechanistic changes that underlie T cell dysfunction as well as whether it is more pronounced in certain anatomical compartments rendering the alcoholic host more susceptible to specific pathogens. A critical barrier to understanding the relationship between excessive ethanol drinking and T cell dysfunction is the availability of within-subject comprehensive, longitudinal data sets. The rhesus macaque model of ethanol self- administration developed by our Co-Investigator, Dr. Grant, is a robust model wherein animals consume high doses of ethanol for >20 months and can provide these data sets. The studies proposed in this application will address fundamental questions of T cell dysfunction both in the peripheral blood and mucosal sites during chronic ethanol consumption and after repeated periods of abstinence followed by open access to ethanol. More specifically, we will first characterize changes in T cell subsets' frequencies and cytokine production longitudinally in peripheral blood and bronchoalveolar lavage as well as cross-sectionally in the gut. We will then explore molecular mechanisms underlying this dysregulation by identifying ethanol-induced changes in microRNA expression patterns within T cell subsets. MicroRNAs have been shown to modulate immune homeostasis during infection. Moreover, changes in microRNA expression have been linked to liver injury due to chronic excessive drinking. The combination of functional and molecular analyses of the peripheral and mucosal T cell compartment will improve our understanding of ethanol-induced changes in T cell function, thereby aiding in the development of novel interventions to improve immunological performance in this at-risk population.