A Novel Role for γδ Intraepithelial Lymphocyyrd in Antibacterial Defense of the Intestine



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The mammalian intestine has coevolved with a highly complex population of enteric bacteria. For the most part, mammals and their intestinal microbiota maintain a mutually beneficial relationship. However, the symbiotic nature of this relationship depends on strict sequestration of intestinal microbes in the gut lumen, and damage to intestinal surfaces by chemical agents or microbial pathogens poses a serious threat of inflammation and sepsis. Therefore, the cells populating the intestinal epithelium have evolved strategies to maintain the integrity of the intestinal epithelium and to limit bacterial invasion. Gamma delta intraepithelial lymphocytes (gamma delta IEL) are unconventional T cells that intercalate under epithelial tight junctions of the intestine. While gamma delta IEL are numerically the most abundant T cell population in the body, their biology in intestinal tissues has remained obscure. The work in this thesis seeks to understand the role of gamma delta IEL in maintaining homeostasis with symbiotic intestinal microbes and in protecting against bacterial pathogens. My findings disclose that intestinal bacteria provide critical regulatory input to gamma delta IEL in the small and large intestine, and direct the production of proinflammatory and antibacterial factors in gamma delta IEL. Additionally, my in vivo studies disclose a novel role for delta gamma IEL in antibacterial defense of the intestine, revealing that gamma delta IEL protect the mucosal barrier in two general ways. First, gamma delta IEL protect against opportunistically invading commensals immediately after mucosal damage. Next, they also function to limit dissemination of invasive bacterial pathogens. My work suggests that a unique feature of gamma delta IEL relative to other intestinal immune cells is their early role in providing protection against invading bacteria immediately after challenge. Taken together, these findings disclose that gamma delta IEL participate in multifaceted antibacterial responses to promote beneficial host-microbial relationships in the intestine.