Investigating the Abundance, Fate, and Function of Secondary Lymphoid Organ Resident Memory T cells

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Project Summary/Abstract: Despite global efforts to curtail emerging and reemerging pathogens, rationale vaccine design has failed to overcome devastating intractable diseases such as malaria, HIV, and tuberculosis. Memory T cells established after natural infection or vaccination contribute to protection against reinfection. Therefore, manipulating vaccine-elicited T cell immunosurveillance may provide protection against intracellular pathogens and might offer a strategy to bolster humoral-mediated vaccines. However, deep understanding of memory CD8 T cell migration will be critical to exploit T cells for next generation vaccine designs. For sixty years, we have understood that lymphocytes recirculate through blood and secondary lymphoid organs (SLO). However, memory T cells parked in the stromal and parenchymal compartments of barrier tissues, known as resident memory T cells (TRM), dominate nonlymphoid tissue (NLT) surveillance and contrast this paradigm. Although central memory T cells (TCM) migrate through blood and lymph, we and others have recently shown that SLO are also patrolled by nonrecirculating TRM ( SLO TRM), which may constitute a major reassessment of LN immunosurveillance. SLO TRM, are broadly distributed following systemic infections and may contribute a substantial fraction to the memory T cell pool in human LNs, but the roles of SLO TRM in immunity are unknown. Owing to their distinct migration properties, I hypothesize that SLO TRM play specialized roles in anamnestic immune responses compared to recirculating memory populations. Aim 1 will rigorously address the abundance and microanatomical localization of SLO TRM after diverse pathogen experiences and identify markers that reliably denote LN residence in ‘dirty’ mice. Aim 2 will test the hypothesis that SLO TRM are poised to migrate to their upstream NLT upon reactivation. And, Aim 3 will address the protective functions of SLO TRM upon reinfection. With implications for vaccine design and assessment, these studies will constitute some of the first investigations into SLO TRM biology. Most importantly, this proposal will serve as an ideal medium for predoctoral training. I will execute this fellowship at the University of Minnesota in the laboratory of David Masopust, Ph.D., a world-leader in the study of memory T cell immunosurveillance. With the combined support of the University’s Center for Immunology, the Microbiology, Immunology, and Cancer Biology Ph.D. program, and Dr. Masopust, I will receive personalized training to facilitate an efficient transition to the next stage of my research career. My long-term career goal is to obtain a faculty position at an academic research institution and direct innovative basic science with an emphasis in immunology.