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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Rothermel, Annette L
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Beura, Lalit K; Mitchell, Jason S; Thompson, Emily A et al. (2018) Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat Immunol 19:173-182
Beura, Lalit K; Wijeyesinghe, Sathi; Thompson, Emily A et al. (2018) T Cells in Nonlymphoid Tissues Give Rise to Lymph-Node-Resident Memory T Cells. Immunity 48:327-338.e5
Steinert, Elizabeth M; Thompson, Emily A; Beura, Lalit K et al. (2018) Cutting Edge: Evidence for Nonvascular Route of Visceral Organ Immunosurveillance by T Cells. J Immunol 201:337-342
Jameson, Stephen C; Masopust, David (2018) Understanding Subset Diversity in T Cell Memory. Immunity 48:214-226
Beura, L K; Rosato, P C; Masopust, D (2017) Implications of Resident Memory T Cells for Transplantation. Am J Transplant 17:1167-1175
Rosato, Pamela C; Beura, Lalit K; Masopust, David (2017) Tissue resident memory T cells and viral immunity. Curr Opin Virol 22:44-50
Masopust, David; Sivula, Christine P; Jameson, Stephen C (2017) Of Mice, Dirty Mice, and Men: Using Mice To Understand Human Immunology. J Immunol 199:383-388
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-?. Nat Immunol 17:414-21
Hondowicz, Brian D; An, Dowon; Schenkel, Jason M et al. (2016) Interleukin-2-Dependent Allergen-Specific Tissue-Resident Memory Cells Drive Asthma. Immunity 44:155-166
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

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