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Cd4 T Cell Interaction With Intestinal Microbes Under Homeostasis And Inflammation, Jiani Chai

Arts & Sciences Electronic Theses and Dissertations

Specific gut commensal bacteria improve host health by eliciting mutualistic regulatory T (Treg) cells responses. However, the bacteria that induce effector T (Teff) cells during inflammation are unclear. Here, we addressed this by analyzing bacterial-reactive T cell receptor (TCR) transgenic cells and TCR repertoires in a murine colitis model. Unexpectedly, we found that mucosal-associated Helicobacter species triggered both Treg responses during homeostasis and Teff responses during colitis, as suggested by an increased overlap between the Teff/Treg TCR repertoires with colitis. In fact, 4/6 Treg TCRs tested recognized mucosal-associated Helicobacter species in vitro and in vivo. By contrast, the marked expansion …

Negative Regulators Of Colonic Peripheral Regulatory T Cell Development, Teresa Lei Ai

Arts & Sciences Electronic Theses and Dissertations

Peripheral Treg cells (pTreg cells) maintain immune homeostasis at mucosal interfaces, where they can develop upon activation of naïve CD4+ T cells by bacteria antigen. However, the cellular and molecular requirements that govern their differentiation in inflamed and homeostatic contexts require further elucidation. To circumvent uncertainties in existing methods of distinguishing pTreg cells from thymic Treg cells (tTreg cells), we analyzed monoclonal cell populations of CT2 and CT6 transgenic (Tg) cells that develop into pTreg cells in response to different species of endogenously presented Helicobacter antigen. In our comprehensive assessment of multiple intestinal inflammatory models, including infections and physical injury, …

Characterizing The Role Of The T Cell Receptor Repertoire In T Cell Development And Function, Benjamin David Solomon

Arts & Sciences Electronic Theses and Dissertations

Expansion and memory of immune cells in response to stimulation of diversified antigen receptors is the hallmark of adaptive immunity. Here, we use antigen receptor sequencing and in vivo analysis of monoclonal cell populations to elucidate the development and function of two T cell populations: Foxp3+RORγt+ CD4+ T cells and γδ T cells. Foxp3+RORγt+ T cells have recently been characterized as an immunoregulatory population highly enriched in the colon lamina propria. However, their developmental origin and relation to RORγt- Treg and RORγt+ TH17 cells remains unclear. Here, we show that despite sharing a subset of TCR specificities with TH17 cells, …

Molecular Mechanisms Mediating The Effects Of Acute Dietary Vitamin A Deficiency On A Defined Model Human Gut Microbiota, Matthew Charles Hibberd

Arts & Sciences Electronic Theses and Dissertations

Micronutrient deficiencies represent a form of "hidden hunger" that afflict two billion people worldwide. To test the hypothesis that dietary micronutrient deficiency has differential effects on members of the human gut microbiota, a consortium containing 92 sequenced phylogenetically diverse bacterial strains was introduced into germ-free mice. Recipient animals were subjected to a diet oscillation that began with highly defined micronutrient-sufficient diet followed by a derivative diet with one of four types of single micronutrient deficiency, or a diet representing combined deficiencies, followed by return to the original sufficient diet. Times-series studies of microbial community structure and transcriptome revealed that acute …

Characterizing The Role Of Sialylated Milk Glycans And The Infant Gut Microbiota In Growth And Metabolism, Mark Richard Charbonneau

Arts & Sciences Electronic Theses and Dissertations

Undernutrition is a pressing and pervasive global health problem. The pathogenesis of this disease remains unclear, but epidemiologic studies indicate that it is not due to food insecurity alone. Moreover, current therapeutic interventions have limited efficacy in preventing or ameliorating the long-term sequelae of undernutrition, including stunting and cognitive deficits. Recent culture-independent studies have demonstrated that the normal postnatal pattern of gut microbiota development is disrupted in children with undernutrition, leading to the proposal that perturbations in gut microbiota development impairs healthy growth of the host. Human breast milk contains a diverse repertoire of free and conjugated human milk oligosaccharides …

A Gnotobiotic Mouse Model For Studying The Effect Of Human Gut Community Ecology On A Pathobiont, Bacteroides Fragilis, Vitas Wagner

Arts & Sciences Electronic Theses and Dissertations

ABSTRACT OF THE DISSERTATION

A Gnotobiotic Mouse Model for Studying the Effect of Human Gut Community Ecology on a Pathobiont, Bacteroides fragilis

by

Vitas Wagner

Doctor of Philosophy in Biology and Biomedical Sciences

Evolution, Ecology, and Population Biology

Washington University in St. Louis, 2015

Professor Jeffrey I. Gordon, Chair

Childhood undernutrition represents a pressing global health challenge. Epidemiologic studies have shown that undernutrition is not due to food insecurity alone, but rather represents a complex set of interactions between intra- and intergenerational factors. The gut microbiota has been implicated as one such factor. This thesis tested the hypothesis that enteropathogen …

Β-Lactamase Gene Exchange Within The Enterobacteriaceae, Mitchell William Pesesky

Arts & Sciences Electronic Theses and Dissertations

Antibiotic resistance represents a grave threat to modern medicine’s control over infectious disease. Pathogens of the Enterobacteriaceae have proven particularly problematic as they can cause a wide variety of infections, and they can be, in some cases, resistant to all antibiotics recommended for use against them. A major part of the threat posed by the Enterobacteriaceae is their ability to exchange resistance genes by horizontal gene transfer (HGT). HGT has allowed some Enterobacteriaceae to quickly accumulate resistance against diverse antibiotics, and then to spread their resistance gene collection to other pathogenic strains. I explore three aspects of how HGT has …

Characterizing The Fitness Landscapes Of Gut Symbionts In Defined Community And Diet Contexts, Meng Wu

Arts & Sciences Electronic Theses and Dissertations

A species' niche is the description of all the environmental conditions required to permit a population of that species to persist, including the effects of the population on those conditions. This definition includes the species' resource requirements, as well as stress tolerances and interactions with other species acting as competitors, predators, parasites, and mutualists. The human gut microbiota serves as a microbial `metabolic organ' tasked in part with the biotransformation of many components of our diet. Relatively little is known about the factors that allow members of the human gut microbiota to persist in a habitat that experiences marked changes …