Thymic and Peripheral Aspects of T Cell Aging and Rejuvenation

整体——抽象

OVERALL- Abstract Infectious disease, cancer, and autoimmune disorders affect hundreds of millions of older adults. They reduce length and quality of life across the globe and inflict a massive economic burden on society, as vividly exemplified by the SARS-CoV-2 pandemic, that has claimed 93.1% of its victims amongst those 50 years and older, and 74.4% in those 64 and older. Yet, despite decades of research, restoring protective immunity in older adults has remained elusive. One critical factor contributing to age-related immune decline is a loss of naïve T (Tn) cell numbers and function, and their rejuvenation is highly desirable in order to enhance protective immunity and overall healthspan in older adults. The renewal of this T cell Rejuvenation Program Project is centered on two key questions: (1) why do Tn cell numbers and function deteriorate with age; and (2) what can be done about it? The premise of the program is that Tn cell aging is multifactorial and that it can only be resolved by targeting multiple defects. Thymic involution and the resulting decline in T cell production is the earliest event leading to immunosenescence. This reduction is compounded by a decline in bone marrow function, as well as by defects in Tn cell maintenance and function in the periphery. These deficiencies combine to erode the ability of the older immune system to detect and eliminate infectious agents and neoplastic cells, and to properly guard against autoimmunity. In the first program period, we strongly confirmed our initial hypotheses that lymphoid organ stromal elements deteriorate earlier than previously thought, and in a manner to decisively erode immunity, with aging. We will build on the synergy and success of the initial program period, where discoveries in one project are critically informing science in others, and continue to identify mechanistic reasons behind reduced central and peripheral lymphoid organ function with aging. We will then develop combined strategies to ameliorate these defects to improve immune defense in the elderly. Our hypothesis is that mechanistic dissection of defects in both thymic production AND peripheral Tn cell maintenance is required to devise and test effective interventions for T cell rejuvenation in the elderly. Three integrated projects led by experts in the field, supported by four cutting-edge cores, will test this hypothesis and achieve the following Program Goals: 1. Define mechanistic changes in primary and secondary lymphoid organ aging; 2. Determine the endogenous regenerative capacity of thymic and secondary lymphoid organ stroma over the lifespan; 3. Relate the progression of murine thymus, lymph node (LN) and T cell aging phenotypes to humans; and 4. Devise and test rejuvenation strategies to improve thymopoiesis, T cell survival and peripheral T cell maintenance and function, so as to enhance protective immunity. Over this support period, the above goals will provide a wealth of basic knowledge that will be translated to preclinical models and be poised for translation to older adults.