The mucosal immune system is constantly exposed to a wide range of commensal and potentially pathogenic microbial species. This chronic exposure to inflammatory mediators and nonpathogenic organisms makes generation of an appropriate immune response critical in maintaining a balance between elimination of harmful pathogens and regulating responses to nonpathogenic organisms. While Listeria monocytogenes (LM) (a category B Biodefense priority pathogen) is one of the most widely utilized pathogens for examining T cell immune responses, little is known about induction of the mucosal CDS T cell response after oral infection. The overall hypothesis to be tested is that effector CDS T cell subsets are differentially regulated by mucosal environmental cues to promote rapid local protection. We will address this hypothesis using a new oral infection model that more closely mimics the human infection.
The specific aims of the project are:
Aim 1 : To define the anatomical events leading to generation of protective mucosal CDS T cell memory.
Aim 2 : To understand the dynamics of CDS T cell priming in response to oral bacterial infection.
Aim 3 : To define the mechanisms regulating development of protective mucosal CDS memory T cells. The studies proposed will examine the eariiest events of CDS T cell differentiation through memory T cell homeostasis and recall to secondary challenge. Examining the induction of effector T cells and the maintenance and recall of memory T cells to a bona fide gut pathogen that closely mimics human infection is critical for a better understanding of CDS T cell immunity in the intestinal mucosa. The knowledge gained from this proposal has broad application potential ranging from understanding the immune response to intestinal pathogens to mucosal vaccine designs.
This project will define the parameters controlling the immune response to an intestinal bacterial infection transmitted through ingestion of the pathogen. The mouse model used recapitulates the human infection and therefore has direct relevance to understanding mucosal immunity and vaccination.
|Benoun, Joseph M; Peres, Newton G; Wang, Nancy et al. (2018) Optimal protection against Salmonella infection requires noncirculating memory. Proc Natl Acad Sci U S A 115:10416-10421|
|Ménoret, Antoine; Buturla, James A; Xu, Maria M et al. (2018) T cell-directed IL-17 production by lung granular ?? T cells is coordinated by a novel IL-2 and IL-1? circuit. Mucosal Immunol 11:1398-1407|
|Svedova, Julia; Ménoret, Antoine; Mittal, Payal et al. (2017) Therapeutic blockade of CD54 attenuates pulmonary barrier damage in T cell-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 313:L177-L191|
|Shinde, Paurvi; Liu, Wenhai; Ménoret, Antoine et al. (2017) Optimal CD4 T cell priming after LPS-based adjuvanticity with CD134 costimulation relies on CXCL9 production. J Leukoc Biol 102:57-69|
|Liu, Wenhai; Menoret, Antoine; Vella, Anthony T (2017) Responses to LPS boost effector CD8 T-cell accumulation outside of signals 1 and 2. Cell Mol Immunol 14:254-253|
|Lee, Seung-Joo; Benoun, Joseph; Sheridan, Brian S et al. (2017) Dual Immunization with SseB/Flagellin Provides Enhanced Protection against Salmonella Infection Mediated by Circulating Memory Cells. J Immunol 199:1353-1361|
|Romagnoli, P A; Fu, H H; Qiu, Z et al. (2017) Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection. Mucosal Immunol 10:520-530|
|Pham, Oanh H; O'Donnell, Hope; Al-Shamkhani, Aymen et al. (2017) T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria. PLoS Pathog 13:e1006566|
|Risso, Gabriela S; Carabajal, Marianela V; Bruno, Laura A et al. (2017) U-Omp19 fromBrucella abortusIs a Useful Adjuvant for Vaccine Formulations againstSalmonellaInfection in Mice. Front Immunol 8:171|
|Benoun, Joseph M; Labuda, Jasmine C; McSorley, Stephen J (2016) Collateral Damage: Detrimental Effect of Antibiotics on the Development of Protective Immune Memory. MBio 7:|
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