Regulation and Function of Oral Resident Memory T Cells

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Project Summary/Abstract Memory T cells chronicle an individual’s infectious past and afford protection to reinfection. Historically defined in blood and subdivided based on their ability to access secondary lymphoid organs, an additional mechanism of T cell immunosurveillance has more recently been described. Here, memory T cells forgo systemic recirculation in exchange for durable residence in non-lymphoid tissues (NLT). Such tissue resident memory T cell (TRM) provide a mechanism for stockpiling immunity within specific barrier compartments commonly exploited by pathogens as portals of entry into the body. TRM function by rapidly intercepting invading pathogens and orchestrating collaborative immune responses. Within NLT, T cell immunosurveillance is predominated by TRM where they accelerate protection against reinfection, may be associated with tumor control, and may also facilitate the persistence of certain allergic and autoimmune diseases. These observations have bolstered TRM as major targets for vaccination. The therapeutic manipulation of TRM holds tremendous promise for the treatment of organ-specific immunological disorders, autoimmunity, and solid cancers. While extensively studied in other mucosal sites, there is presently a fundamental void in our understanding of the ontogeny, function, and therapeutic implications of oral-mucosal TRM. Considered amongst the most architecturally and biologically varied tissue sites in the body, the mouth is continuously bombarded by myriad dietary and environmental antigens and harbors diverse microbial communities. Moreover, the mouth and salivary glands can be colonized by bacterial, fungal, and viral pathogens including herpes simplex virus and human papilloma virus. Given their well- documented and critical functions in mediating barrier immunosurveillance in other NLT, oral TRM are likely to play a major role in antiviral immunity and oral immune homeostasis. TRM may also perpetuate chronic immune responses observed in periodontal disease and oral lichen planus. However, addressing their role in these clinically relevant settings has suffered from a lack of animal models which would facilitate the generation of sufficient oral TRM to manipulate and study. I have bridged this gap by developing a novel oral ‘prime-pull’ strategy, the first of its kind, for generating large quantities of tractable TRM in the oral mucosa. Leveraging this innovative approach, I will address outstanding fundamental questions regarding oral TRM biology with translational potential for human oral health. During the K99 phase, I will define the recruitment and retention signals governing oral TRM with implications for depleting pathogenic subsets (Aim 1). Experiments spanning the K99/R00 phases will investigate the consequences of oral TRM reactivation in shaping the microbial and inflammatory landscape of the mouth with clinical relevance for recrudescent oral infections and oral cancer (Aim 2). Work conducted in the R00 phase will define the role of oral TRM in the pathogenesis of periodontitis, the most common chronic inflammatory condition worldwide (Aim 3). In summary, work outlined in the proposal will pave a path forward towards my goal of developing therapeutic interventions targeting oral TRM.