Mucosal tissues represent the most common sites of infection. Establishing memory CD8 T cells at mucosal sites through vaccination may be critical for protecting the host against certain infections, including HIV. However, surprisingly little is known about the properties of memory CD8 T cells within the gastrointestinal and genital mucosa, the mechanisms that regulate their establishment, maintenance and differentiation state, and most importantly, what mucosal memory CD8 T cells within these tissues actually contribute to protection from local infections. These gaps in knowledge represent a major barrier to the successful development of protective CD8 T cell vaccines against mucosal pathogens. The main goal of this proposal is to use mouse models of infection to determine how protective CD8 T cell immunity is regulated at mucosal surfaces. To address this question, we will: 1) define mechanisms that regulate location-specific mucosal memory CD8 T cell differentiation states, 2) determine processes that govern CD8 T cell migration and maintenance within mucosal tissues, and 3) test the relationship between memory CD8 T cell location and differentiation state and the ability of the host to protect itself against intracellular pathogens encountered at mucosal surfaces. Specifically, we will test the hypothesis that establishing protective CD8 T cell immunity at mucosal portals of infection is controlled by three processes: developmental cues during priming within lymphoid tissues, the regulation of antigen-specific T cell trapping within mucosal parenchyma, and location specific cues that vary among different mucosal tissues and control memory T cell differentiation programs. Our studies may provide information for the design of vaccines that optimally establish protective CD8 T cell immunity at mucosal portals of infection.

Public Health Relevance

Mucosal tissues represent the most common site of infections. These studies will examine how the establishment, maintenance, and differentiation of memory CD8 T cells is regulated within mucosal tissues, and will test the ability of mucosal memory CD8 T cells to protect the host upon local exposure to intracellular pathogens. Achieving these aims will benefit the design of CD8 T cell vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084913-03
Application #
8211056
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Rothermel, Annette L
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$373,725
Indirect Cost
$126,225
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Schenkel, Jason M; Fraser, Kathryn A; Casey, Kerry A et al. (2016) IL-15-Independent Maintenance of Tissue-Resident and Boosted Effector Memory CD8 T Cells. J Immunol 196:3920-6
Beura, Lalit K; Hamilton, Sara E; Bi, Kevin et al. (2016) Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532:512-6
Hondowicz, Brian D; An, Dowon; Schenkel, Jason M et al. (2016) Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma. Immunity 44:155-66
Mohammed, Javed; Beura, Lalit K; Bobr, Aleh et al. (2016) Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β. Nat Immunol 17:414-21
Rosato, Pamela C; Beura, Lalit K; Masopust, David (2016) Tissue resident memory T cells and viral immunity. Curr Opin Virol 22:44-50
Beura, Lalit K; Anderson, Kristin G; Schenkel, Jason M et al. (2015) Lymphocytic choriomeningitis virus persistence promotes effector-like memory differentiation and enhances mucosal T cell distribution. J Leukoc Biol 97:217-25
Steinert, Elizabeth M; Schenkel, Jason M; Fraser, Kathryn A et al. (2015) Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance. Cell 161:737-49
Anderson, Kristin G; Mayer-Barber, Katrin; Sung, Heungsup et al. (2014) Intravascular staining for discrimination of vascular and tissue leukocytes. Nat Protoc 9:209-22
Schenkel, Jason M; Masopust, David (2014) Tissue-resident memory T cells. Immunity 41:886-97
Schenkel, Jason M; Fraser, Kathryn A; Masopust, David (2014) Cutting edge: resident memory CD8 T cells occupy frontline niches in secondary lymphoid organs. J Immunol 192:2961-4

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