ORCID

http://orcid.org/0000-0002-1846-2583

Date of Award

Spring 5-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The environment is well recognized to modulate immune responses within the intestinal mucosa in a general fashion. However, the connection between the effects of the environment on the immune response directed towards specific intestinal microbes is unclear. Progress in this area has been hampered by the lack of a model system in which the immune responses to a specific antigen in a gut symbiont can be examined. To this end, we developed a novel CD4+ T cell model, termed BθOM, that is specific for a dominant antigen in the gut symbiont Bacteroides thetaiotaomicron (B. theta). In this work, we use the BθOM T cell model to elucidate how two key environmental factors—capsular polysaccharides (CPSs) and diet—regulate the immune response to a dominant antigen in B. theta.

We unbiasedly investigated if all CPSs on B. theta can modulate the immune response to a dominant B. theta antigen. Acapsular B. theta (Acap), which lacks all B. theta CPSs, stimulated BθOM T cells more strongly than wild-type B. theta. Many single CPS-expressing B. theta strains were anti-stimulatory and weakly activated BθOM T cells, but a few strains were pro-stimulatory and strongly activated BθOM T cells just as well or better than Acap. B. theta strains expressing an anti-stimulatory CPS blocked antigen delivery to the immune system, which could be rescued by Fc receptor-dependent antibody opsonization. All single CPS-expressing B. theta strains stimulated the innate immune system in a MyD88-dependent manner, but B. theta strains with an anti-stimulatory CPS activated the innate immune system more weakly than B. theta strains with a pro-stimulatory CPS. Individually expressing CPSs on B. theta outer membrane vesicles (OMVs) also modulated immune responses to dominant antigen. Moreover, CPS expression on B. theta regulated the activation of antigen-specific and polyclonal T cells as well as clearance of dominant antigen in vivo. These studies demonstrate that the immune responses to specific bacterial antigens can be modulated by a diverse set of CPSs.

We also examined if dietary regulation of the expression of dominant microbial antigens can control the CD4+ T cell immune response to these bacterial antigens. Adoptively transferred BθOM T cells proliferated in the colon and colon draining lymph node (cdLN) in healthy mice colonized with B. theta and differentiated into regulatory (Treg) and effector T (Teff) cells. Depletion of B. theta-specific Tregs resulted in colitis, demonstrating that a single protein expressed by B. theta can drive differentiation of Tregs that self-regulate Teffs to prevent disease. We identified the B. theta antigen recognized by BθOM T cells to be BT4295, an outer membrane protein contained in one of B. theta’s many polysaccharide utilization loci. Interestingly, the expression of BT4295 is regulated by nutrients, with glucose being a strong catabolite repressor of BT4295 expression. Despite similar B. theta colonization levels as control mice, mice fed a high glucose diet had greatly reduced activation of BθOM T cells in the colon and cdLN. These studies establish that the immune response to specific bacterial antigens can be modified by the expression of different CPSs as well as dietary changes that alter the antigen expression in the microbe. These findings suggest that targeting the microbiota environment to reduce the delivery of dominant antigens to the immune system may be a potential therapeutic strategy for inflammatory bowel disease.

Language

English (en)

Chair and Committee

Paul Allen

Committee Members

Maxim Artyomov, Juliane Bubeck-Wardenburg, Chyi-Song Hsieh, Thaddeus Stappenbeck,

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