Dedifferentiation Of Cytotoxic Lymphocytes Into Central Memory Cd8+ T Cells: Lessons From Antiviral T Stem Cells On The Architecture Of Aging & Immunotherapy

Startling advances in biological gerontology coupled with the ongoing, global demographic transition to older populations have intensified humankind’s ancient quest to understand the nature of aging. This dissertation explores mechanisms of mortality through the prism of immunology. To effect defense against pathogens both exogenous and endogenous, the adaptive immune system leverages the tremendous proliferative capacity with which it is endowed to generate terminally differentiated lymphocytes that potently eliminate or suppress threats to organismal health. This proliferative capacity derives from the integrity of genomically encoded information, and, while considerable, is not infinite: it can be depleted with age and following repeated rounds of antigen-driven proliferation, for example, when driven by recurring or persisting microbial infections, or cancer. In the studies detailed herein, genome integrity homeostasis was probed during the immune response to viral infection. CD8+ T cells were observed to experience significant DNA damage in the course of their attempts to control viral replication. Multiparametric flow cytometry identified a rare population of antigen-specific T stem cells that might represent an evolutionary strategy to minimize genotoxicity. The programming, metabolic profile, anatomic localization, proliferative capacity, and ontogeny of these T stem cells were analyzed in relation to previously established effector, memory precursor, and central memory populations. Developmentally, T stem cells were able to self-renew and both give rise to abundant cytotoxic effector CD8+ T cells in the presence of antigen as well as contribute to the pool of long-term central memory CD8+ T cells following antigen clearance. Remarkably, partially-differentiated transit-amplifying effector CD8+ T cells also contributed to long-term central memory, in a process of apparent dedifferentiation. Programmatically, T stem cells were endowed with superior expression of multiple genome maintenance and repair activities, including heightened responsiveness to DNA strand breaks, telomerase expression, and suppression of potentially mutagenic transposition by the ancient LINE-1 retrotransposon. Together, these features suggest that this characteristic of amplified genome integrity surveillance may be a fundamental feature of somatic stem cells broadly, and important for the long-term maintenance of antigen-experienced T cell populations in particular. Additionally, despite relative proliferative quiescence, T stem cells unexpectedly manifested intense signaling flux. This was associated with robust expression of a panoply of both stimulatory and inhibitory cell surface receptors, including PD-1. Intensified signaling consequent to genetic ablation of inhibitory receptors compromised T stem cell viability during acutely-resolving viral infections. These findings hold significant implications for basic understanding of pathogen-driven peripheral T cell differentiation, formation of long-term immunological memory, and aging; and for the design of therapeutic, prophylactic, and diagnostic applications intended to further the cause of maximizing healthy human lifespan