Ketogenic diet activates protective ?d T cell responses against influenza virus infection

Influenza A virus (IAV) infection-associated morbidity and mortality are a key global healthcare concern, necessitating the identification of novel therapies capable of reducing the severity of IAV infections. In this study, we show that the consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. KD feeding resulted in an expansion of ?d T cells in the lung that improved barrier functions, thereby enhancing anti-viral resistance. Expansion of these protective ?d T cells required metabolic adaptation to a ketogenic diet, as neither feeding mice a high-fat high-carbohydrate diet nor providing chemical ketone body substrate that bypasses hepatic ketogenesis protected against infection. Therefore, KD mediated immune-metabolic integration represents a viable avenue towards preventing or alleviating influenza disease. Overall design: We profiled IAV-infected whole lung tissue and gdT cells sorted from infected lungs 3 days post-infection.