Microbiota-gamma delta IEL-Paneth cell axis in host antimicrobial response

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PROJECT SUMMARY. Maintenance of an intact intestinal barrier is critical to prevent microbial activation of mucosal immunity. gd intraepithelial lymphocytes (IEL) migrate extensively within the epithelial compartment to serve as a first line of defense against luminal antigens and invasive enteric microbes, and have been implicating in regulating Paneth cell secretion of antimicrobial peptides. Although microbial-derived molecules contribute to gd IEL homeostasis, specific commensal bacteria have yet to be associated with alterations in gd IEL number and/or function. Moreover, the extent to which gd IEL-mediated signaling influences Paneth cell function has yet to be explored. In preliminary data generated for this application, we identified 5 amplicon sequence variants (ASV) that are strongly associated with the expansion of gd IELs under homeostatic conditions. We also show that epithelial cells isolated from WT mice with an expanded gd IEL compartment also exhibit a significant upregulation of genes involved in Paneth cell antimicrobial peptide production and secretion. Therefore, this proposal seeks to identify the contribution of individual commensals to the expansion of the gd IEL compartment and determine the extent of gd IEL-Paneth cell crosstalk in WT mice exhibiting this hyperproliferative phenotype. Using an integrated approach that combines unique mouse models and cutting edge imaging technologies both in vitro and in vivo, these studies will be the first to identify the contribution of individual commensals in the amplification of gd IEL proliferation and surveillance behavior, and elucidate whether gd IELs directly promote Paneth cell function. Developing a better understanding of the microbiota-gd IEL-Paneth cell axis may identify novel therapeutic targets to aid in host defense and help maintain remission in Crohn’s disease patients.