Crosstalk between MAIT cells and the microbiota

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Project Summary/Abstract Career Goals: My overarching career goal is to become an independent investigator at an academic institution where I study how the microbiota impacts the development and function of the immune system, ultimately translating my findings into novel treatments. I also aspire to become an inspirational teacher and mentor. Career Development: In addition to meeting weekly with Dr. Belkaid, I will discuss my progress with my mentors at least once every 6 months for the duration of the award. The NIH has numerous training resources which will be pivotal to my development, including courses and workshops. I will enhance my ability to analyze computational datasets by participating in bioinformatics courses, enroll in courses to improve my teaching and mentoring, and attend seminars on the transition to independence and management. I will further develop my communication skills prior to the K22 award by authoring 2 manuscripts and presenting at least 8 times at seminars and conferences. Environment: The NIH Intramural Research Program has more than 1,200 PIs conducting basic, translational, and clinical research, a plethora of core facilities, and resources for the career development of postdocs. The NIAID Microbiome Program has a gnotobiotic animal facility and a sequencing facility that also provides bioinformatics analysis. There are numerous seminar series featuring external faculty and others that allow trainees to present their research. Prior to the K22 award, I will work in the laboratory of Dr. Belkaid, which is a BSL-2 research space and is adequately equipped to conduct the proposed experiments. Research: Skin infections are the 4th most prevalent cause of disease globally, indicating that cutaneous diseases are a major health concern. In addition to inhibiting colonization by pathogens through competition and the induction of immune responses, the microbiota promotes immune homeostasis via the release of microbial products. Human skin harbors mucosal-associated invariant T (MAIT) cells, which rapidly produce either Th1- or Th17-associated cytokines in response to microbial vitamin B2 derivatives presented by the MHC-Ib molecule, MR1. We have recently found that IL-17A+ MAIT cells are highly abundant in murine skin and depend on the microbiota. However, the mechanism by which commensals promote MAIT cell development remains unknown. To address this, I will identify microbes that induce MAIT cell development and elucidate the mechanism using an Mr1f/f conditional knockout and other murine models. Administration of these commensals to mice challenged with cutaneous pathogens will establish whether the microbiota can enhance the contribution of MAIT cells to skin immunity, which could have clinical applications due to the high frequency of cutaneous MAIT cells.