Daqi XuFollow

Date of Completion

6-27-2013

Embargo Period

6-27-2015

Keywords

Listeria monocytogenes, PD-L1, CD8 T cell, Batf3, CD8a dendritic cell, CD103, oral infection

Major Advisor

Leo Lefrançois

Associate Advisor

Anthony Vella

Associate Advisor

Kamal Khanna

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Listeria monocytogenes (L.m.) is a food-borne bacterium that can cause severe disease. Nevertheless, recombinant L.m. have been developed as potential vaccine vectors. Due to the importance of the mucosal immune system and the requirement for developing vaccine therapies for cancer and detrimental infections, this thesis focuses on the analysis of innate and adaptive immune responses to intravenous or oral L.m. infection. Costimulation molecules are essential for optimal CD8 T cell responses against L.m. infection. PD-L1 is an important negative regulator of T cell immune responses via interactions with PD-1 and CD80. However, PD-L1 can also act as a positive costimulator, but the factors determining its effect on activation are unknown. We found that PD-L1 provided costimulation to antigen-specific CD8 T cells independent of CD4 T cell help in response to L.m., but not to Vesicular stomatitis virus infection. Specific blockade of PD-L1 binding to CD80 or/and PD-1 did not recapitulate the effect of a general blockade of PD-L1. The results suggested that PD-L1 plays an important costimulatory role for antigen-specific CD8 T cells during L.m. infection through a distinct receptor or interaction epitope.

In addition, as the natural infection route for L.m. is through ingestion of contaminated food, we also studied the immune response to oral L.m. infection using a murinized L.m.. Initially, infection was limited to the gut mucosa. Intracellular L.m. was initially shuttled through the subcapsular sinus into the interfollicular zones of the mesenteric lymph nodes(MLNs) and subsequently appeared in the T cell zone. In response, an organized cellular architecture rapidly developed in which Ly6G+ neutrophils initially surrounded L.m., followed by formation of an outer zone of CD103+ dendritic cells (DCs) and T cells, indicating a potential antigen presentation site. Dissemination of both L.m. and irradiated L.m., but not Salmonella, to the MLNs required Batf3-dependent DCs, suggesting the existence of a receptor-mediated pathway for L.m. acquisition, rather than provision of a replicative niche. In sum, our data characterized the organization of innate immune responses to an orchestrated Listeria dissemination pattern in the gut mucosa.

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