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Hardman, Blair

University of British Columbia

The combination of diverse metabolism, large microbial community, and vast surface area make the intestines a complex immunological challenge. Mucosal immune responses must target infections while limiting disruptions to intestinal function or off-target reactions in the antigen-rich environment. Regulation of this balance, which is shaped locally by tissue-specific cues, and distally in secondary lymphoid organs, is not fully understood. Exploring these concepts promises insights into vaccine development and treatment of inflammatory digestive diseases. Intestinal epithelial cells (IECs) not only maintain a barrier between the external environment and host tissues, they are also active participants in local immune homeostasis. Based on prior observations that IEC-intrinsic canonical and non-canonical NF-κB activation via the kinases IKKβ and IKKα shape the inflammatory tone of immune responses to helminth and bacterial infections, I hypothesized that IEC-intrinsic NF-κB signalling may be a conserved mediator of inflammation elicited by enteric infections. However, in the context of acute or persistent intestinal murine norovirus (MNV strain CW3 or CR6) infection, there was no detectable effect on viral loads or antiviral CD8⁺ effector T cells in the absence of either IKKα or IKKβ in IECs. To assess how antiviral CD8⁺ T cell distribution along the length of the gastrointestinal (GI) tract is regulated, I used tissue microscopy and flow cytometry following infection with MNV CW3 and CR6. I found that the initial intestinal site of infection dictates which node of the mesenteric lymph node (MLN) complex hosts the earliest CD8⁺ T cell responses. However, later stages of T cell expansion and localization within the GI tract are driven by virus-specific behavior. My results suggest that in the absence of systemic infection, antiviral effector cells primed in the spleen are not equipped for intestinal access. Understanding how intestinal access is granted will be valuable in designing oral vaccines while methods of enforcing intestinal immune seclusion may provide a means of preventing or limiting flareups in people with inflammatory digestive diseases. This work outlines avenues of inquiry using MNV strains in a comparative model to contrast CD8⁺ T cell responses and delineate cues which influence the distribution and scale of immune responses.

Text

2024-02-16

Attribution-ShareAlike 4.0 International

http://hdl.handle.net/2429/87453

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-sa/4.0/