T cell surveillance of senescent cells under homeostasis and aging

PROJECT SUMMARY/ABSTRACT RESEARCH: Aging is the single greatest risk factor for a multitude of morbidities. While multifactorial, a central mechanism of aging is cellular senescence, a complex, context-dependent cell fate with important roles in both, physiological and pathological processes. The acute generation and subsequent elimination of senescent cells is usually a physiological, beneficial process associated with accelerated tissue regeneration after injury, but the aberrant senescent cell accumulation is linked to a wide range of pathologies, morbidities, and shortened healthy life spans in mice. The mechanisms governing physiological senescent cell elimination, or their pathological accumulation with age are incompletely understood, particularly in the human context. T cells have emerged as one of the crucial players in controlling and killing senescent cells, however, how senescent cells engage and activate T cells to elicit T cell activities and cytotoxicity is largely elusive. In this proposal, I investigate molecular mechanisms of T cell-mediated surveillance of senescent cells under both physiological and aging conditions. In Aim 1, I will define how various types of senescent cells deploy their secretome to sensitize human T cells toward activation, survival, and retention. Aim 2 will assess co-stimulatory and co-inhibitory interactions between senescent cells and T cells, crucial prerequisites of effective T cell activity or inhibition. In Aim 3, I will perform translational studies in human kidney specimens to elucidate spatially resolved T cell surveillance of renal senescent cells as well as mechanistic studies in isolated primary renal cells. CANDIDATE: This proposal integrates my Ph.D. expertise in cellular senescence with my post-doctoral work on T cell aging and allows me to build an independent, unique research niche. However, to realize this goal, I require additional protected time and new research and professional skills. Here, I describe a detailed plan for my transition to independence. The research during the K99 phase will be conducted at Mayo Clinic, the world’s top-ranked hospital and an ideal institution for translational, human research on aging. The objectives of this proposal are to i) gain additional mentored research and career training to build an independent translational research program dedicated to age-related T cell dysfunction contributing to pathological senescent cell accumulation in humans; ii) perform a series of experiments to uncover molecular mechanisms of T cell engagement by senescent cells under optimal conditions and delineate the impact of T cell aging on senescent cell immune evasion. Completion of the proposed aims allows me to build a strong foundation on T cell surveillance of senescent cells enabling me to discover key mechanisms of senescent cell immune escape. This will leave me well-positioned to become an independent investigator, securing competitive funding, advancing the field of senescence immunosurveillance, and contributing towards my long-term research goal of promoting healthy aging through the development of immunotherapies targeting pathological senescent cells.