Tissue resident memory T cells (TRM) are a newly define lineage of memory T cells that reside predominantly in non-lymphoid tissues (NLT), rarely recirculate and are the main surveyors of NLT where they are poised to elicit a potent and rapid response upon encountering reinfection. TRM are abundant in mouse and human and have been described in the central nervous system (CNS). While T cells in the CNS have been implicated in both health and disease, there persists a gap in knowledge regarding TRM regulation and function in the brain. The applicant?s long-term goal is to understand immune cell function and surveillance in the CNS so that improved therapeutic strategies can be developed against neurotropic infections and CNS autoimmunity. The objective of this proposal is to establish a foundational understanding of TRM function and regulation in the CNS. This proposal builds on the finding that expression of the inhibitory receptor, PD-1, is uniquely high on brain TRM and will test the hypothesis that PD-1 signlaing functions to restrain the magnitude of TRM reactivation, protecting against neurologic immunopathology. This hypothesis will be tested by integrating techniques examining transcriptional and cellular changes as well as whole animal physiology.
Aim 1 will define TRM reactivation, assess how PD-1 signaling modulates this, and evaluate the impact on activation of surrounding immune cells and animal cognition.
Aim 2 will investigate the impact of brain TRM reactivation on blood-brain barrier integrity, the influx of circulating immune mediators (immune cells and antibody), and how PD-1 signaling may influence this. By understanding the regulation and function of brain TRM, a foundational knowledge can be built upon to contextualize the role of TRM in pathologic and protective settings. The applicant?s pre-doctoral training in virology and innate neuroimmunology, fused with current post-doctoral training in tissue resident adaptive immunity makes her well equipped to tackle large gaps in knowledge regarding neuro-immune interactions with a unique perspective and armory of techniques. The applicant will continue to work with her mentor and take advantage of opportunities at her current institution to develop skills necessary for successful transition to an independent investigator. In summary, the K22 Career Transition Award will allow the applicant to attain her scientific and career goals by providing a base of research and training to establish an independent NIH-funded program in the field of neuroimmunology.

Public Health Relevance

The aim of this study is to understand the function and regulation of resident T cells (TRM) in the brain, a once thought of immune privileged organ. T cells have been implicated in numerous settings including neurotropic infections, autoimmunity, Alzheimer?s, pain and even normal brain homeostasis however despite this, very little is known about how T cells, in particular TRM, function in the brain. Deepening our understanding of brain TRM functions will enable us to contextualize them in the setting of these disease states and provide a platform for vaccine design against neurotropic infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Career Transition Award (K22)
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Transplantation Biology & Immunology-2 (AITC)
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Gondre-Lewis, Timothy A
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Dartmouth College
Schools of Medicine
United States
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