The major entry point for many human pathogens is through gastrointestinal mucosal surfaces. This barrier tissue is also highly enriched with conventional (CD8 and CD4) and unconventional (gamma delta, γδ) T cell populations that are poised for rapid control in case of barrier breach. Thus, a goal of vaccination against foodborne pathogens is to leverage mucosal T cells to prevent infection. As such, understanding the mechanisms of immunologic protection at this site is essential for designing effective vaccination schemes. My laboratory is focused on elucidating the processes regulating T cell memory in mucosal and barrier tissues. We seek to understand the processes of effector T cell generation, establishment of memory, and memory homeostasis within the intestinal mucosa. My lab primarily utilizes foodborne infection with pathogens such as Listeria monocytogenes, Salmonella enterica (Typhimurium), and Yersinia pseudotuberculosis to probe conventional and unconventional T cell responses in the gastrointestinal system. These pathogens provide an excellent opportunity to understand the biology of intestinal T cell immunity and apply this knowledge to human pathogens, inflammatory disorders of the intestines, and gastrointestinal tumors.
I. Memory CD8 T cells
- BATF3 regulation of memory T cell development: The transcription factor BATF3 regulates CD8 T cell responses through cell extrinsic and intrinsic pathways. BATF3 regulates the development of a conventional DC subset (cDC1) that promotes the induction of effector CD8 T cells during foodborne L. monocytogenes infection. My lab was the first to report that cell intrinsic BATF3 also promotes the development of CD8 T cell memory, in part by regulating apoptosis during the contraction phase of an immune response. A current project continues to explore how this transcription factor regulates T cell responses.
- Licensing of resident memory T cell development: Foodborne L. monocytogenes infection induces a robust intestinal CD8 T cell response that is predominately composed of memory precursor cells that rapidly upregulate a marker of epithelial T cell residency, CD103. However, intravenous infection with the same pathogen induces minimal CD103 expression and reduced residency. A current project focuses on understanding the impact of T cell activation in gut draining lymph nodes, T cell licensing during priming, and T cell migration to and localization within the gut on resident memory formation.
II. Memory γδ T cells
- Specificity: While γδ T cells are thought to predominately behave in an innate fashion, we have recently demonstrated that a distinct subset establishes memory after foodborne L. monocytogenes infection. A current project is currently using T cell receptor sequencing in conjunction with foodborne infection of mice with diverse pathogens including L. monocytogenes, S. enterica, Y. pseudotuberculosis, and Citrobacter rodentium to evaluate the specificity of memory γδ T cells.
- Activation: Memory γδ T cell responses mobilize innate-like γδ T cells expressing nearly invariant T cell receptor, suggesting that these cells are more complex than originally proposed. A unique feature of the memory population elicited by foodborne L. monocytogenes infection is its multifunctional IL-17A and IFNγ response. A current project seeks to understand the factors that shape and govern this unique functional response through the different phases of the immune response to pathogens.
- Subversion by Yersinia spp.: While Y. pseudotuberculosis has been known to subvert phagocyte function for decades, the direct impact of the type 3 secretion system on subversion of adaptive immune cells is less clear. We recently demonstrated that Y. pseudotuberculosis targets a specific subset of γδ T cells to inhibit their effector functions marking a novel mechanism of Yersinia spp. pathogenesis. A current project is elucidating the mechanisms of direct subversion of T cell function.
III. Listeria-based Cancer Vaccines
- Oral vaccines: L. monocytogenes is an attractive and currently utilized vaccine platform. Several intravenous Listeria-based cancer vaccines are currently being tested in clinical trials with promising results on overall patient survival. As oral vaccination is an attractive vaccine delivery route, a current project is assessing the immunogenicity and efficacy of highly attenuated vectors delivered by oral immunization.