Most reinfections are initiated within tissues that comprise a frontline barrier with the outside world, such as the gastrointestinal, respiratory, and genitourinary mucosae. Memory CD8 T cells protect against intracellular pathogens by scanning host cell surfaces, so their migration patterns directly impact their ability to detect reinfection. It was recently discovered that a major lineage of memory CD8 T cells, termed resident memory (TRM), occupies mucosal tissues without recirculating. However, TRM act as first responders against reinfection events that are initiated in barrier tissues, and they greatly accelerate pathogen control and decrease disease. Thus, eliciting TRM may be an important goal for T cell vaccines against mucosal pathogens. Because TRM are not present within the easily sampled peripheral blood, and also because they were previously conflated with recirculating effector memory T cells, TRM have not yet been well characterized. This proposal will address major gaps in our current understanding of TRM. The hypothesis that TRM comprise different subsets, but share lineage defining markers will be tested using model infections in mice, parabiotic surgeries, and transcriptional profiling. Defining and validating bona fide markers will allow othe investigators to examine TRM biology even in systems where monitoring recirculation is impractical, or impossible (e.g. in humans), and will put the field on a firmer molecular foundation. Preliminary data indicating that TRM regulation differs from conventional T cell memories will support investigations into TRM longevity, maintenance requirements, and issues of homeostatic regulation in nonlymphoid tissues; issues with immediate relevance for vaccination. While CD8 T cells are thought to comprise an entirely separate arm of the immune system from antibodies, provocative preliminary data supports the hypothesis that CD8+ TRM act as sensory cells within the mucosae that are capable of rapidly increasing mucosal antibody concentrations in the event of reinfection. This proposal will explore the underlying mechanisms for this novel observation, which may provide further rationale for coupling T cell vaccination approaches with conventional humoral vaccine approaches for protecting against intractable pathogens such as HIV. Lastly, this proposal will test novel hypotheses related to augmenting TRM establishment within desired mucosal sites using a strategy that could be feasibly translated to humans. Practicably achieving this goal is still one of the major ambitions in T cell vaccinology. In summary, significant expertise will be leveraged to pursue fundamental biology into the emerging field of T resident memory, with very high health relatedness and potential for impact. New discoveries made here regarding TRM regulation, defining markers, longevity, function, and permissiveness to manipulation could have wide ranging impact not only for vaccines, but other T cell mediated immunological processes in tissues, including immunopathology, tumor immunosurveillance, and autoimmunity.
This proposal will answer fundamental gaps in current understanding of resident memory CD8 T cells, which protect against mucosal infections. This information will lead to improvements in vaccine design.
| 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 |
| 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 |
| 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 |
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