DECODING AND HARNESSING MICROBIAL TUNING OF T CELL RESPONSES IN EARLY LIFE

Project Summary/AbstractTrillions of microbes reside in and on our body's barrier surfaces. To maintain health our immune system mustestablish tolerance to these commensal microbes but also preserve the ability to mount protective responsesagainst infectious threats. We have found that adaptive immune tolerance is established to skin commensalbacteria but not skin pathogens and that these divergent responses are established upon first encounter withthese microbes early in life. The overarching goal of this proposal is to elucidate the host-directed andmicrobe-directed mechanisms that support adaptive immune tolerance to commensal microbes whilepermitting protective immunity to pathogens, using skin as the tissue of focus. To achieve this we willemploy cutting-edge immunological and microbiological techniques, including in vivo tools to dissect theantigen-specific response to skin bacteria, a new CRISPRi system to genetically modify skin bacteria andidentify key microbial molecules, and a novel pre-clinical platform to examine the impact of microbial productson a human inflammatory skin disease. Ultimately, this high-risk high-reward proposal seeks to inform ourunderstanding of fundamental mechanisms that shape our early `decisions' about tolerance vs. immunity toforeign antigens and identify new therapeutic approaches to modulate these responses for clinical benefit.