Date of Completion

8-6-2013

Embargo Period

7-24-2023

Keywords

Mucosal immunology, memory CD4 T cells

Major Advisor

Leo Lefrancois

Associate Advisor

Robert Clark

Associate Advisor

Kamal Khanna

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

Listeria monocytogenes (LM) is an enteroinvasive pathogen and the cause of listeriosis, a highly fatal food borne infection. Using an oral LM infection model, we show that a subset of blood-borne listeriolysin O (LLO)-specific CD4 T cells transiently express the α4β7 integrin early after infection. Subsequently, antigen-specific CD4 T cells rapidly accumulated and retained long-term in the gut mucosal tissues, and exhibited a robust recall response. These data suggested that priming in the mucosal lymphoid tissues generated a subset of mucosa-seeking CD4 T cells with high memory potential in an IL-15 independent manner. Phenotipically, naive CD4 T cells (CD44low, CD62Lhigh) contained two distinct subsets: Ly6Chigh/CD27high and Ly6Clow/CD27high. At day 9 post-infection, the majority of LLO-specific CD4 T cells in the mucosal tissues were Ly6Clow/CD27low and this population persisted throughout memory. In contrast, LLO-specific CD4 T cells isolated from the spleen and MLNs were comprised of four subsets based on CD27 and Ly6C expression. Mucosal CD27lowLy6Clow CD4 T cells produced IFN-γ and IL-2 while CD27low as well as both Ly6Clow and Ly6Chigh splenic and MLN CD4 T cells expressed the same cytokines as well. Interestingly, IL-17 production increased in mucosal memory CD4 T cells. In the absence of CD69 expression, IL-17 production is substantially increased in mucosal CD4 T cells. However, mixed bone marrow chimera studies indicate that this phenomenon is not a CD4 T cell intrinsic affect. Also, the absence of IL-15 leads to more IL-17 production of mucosal CD4 T cells. Depletion of CD4 T cells leads to a higher bacterial burden in the gut and spleen. These results indicate that antigen-specific intestinal mucosal effector and memory CD4 T cells are phenotypically and functionally distinct compared to their splenic counterparts. Thus, our findings demonstrate an important role for mucosal memory CD4 T cells in protection against oral infection and in maintaining barrier infection.

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