Date of Award
9-18-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
CD8 T cells are a crucial component of the immune system, primarily responsible for executing the effector response against viral infections and cancer. Aging significantly impacts most immune cell types, with particularly dramatic changes observed in CD8 T cells. One major age-related difference is the marked decline in thymus activity, which leads to a substantial reduction in naive CD8 T cells and an increased abundance of memory CD8 T cells. Furthermore, recent work from our lab demonstrated that while young memory CD8 T cells are relatively homogeneous, memory CD8 T cells diverge into two subpopulations: PD1- memory CD8 T cells and PD1+ age-associated CD8 T cells (TAA). The overarching goal of this dissertation was to identify functional features of the two old memory CD8 T cell subsets, investigate the upstream drivers of these changes, and elucidate their physiological significance. This work led to two projects, which are described in this dissertation. First, we discovered a drastic difference in functionality between young and old PD1- memory CD8 T cells. We demonstrated that aged PD1- memory CD8 T cells abandon the requirement for MHC-restricted cytotoxicity and can kill target cells in an antigen-independent manner upon activation. Our findings revealed that, although aged PD1- memory CD8 T cells lack canonical surface markers of activated or effector T cells, they exhibit a transcriptional signature and surface markers akin to pathogenic CXCR6+ CD8 T cells, which are known to mediate liver damage in the NASH model. We also showed that this non-specific killing is executed through a Fas ligand (FasL)-dependent mechanism. We used a mouse model of sterile inflammation to investigate the role of the aged T cell in vivo. Our data indicates that aged memory CD8 T cells promote widespread cell death in old animals, affecting tissue such as the liver and the kidney. Finally, we demonstrated that a similar phenotype can be driven by exposure of young mice to irradiation-induced lymphopenia, suggesting age-related decline of thymic function and naïve CD8 T cell numbers might be causative of non-specific killing phenotype. Second, we investigated the developmental trajectory of PD1+ TAA cells – a population present only in old mice. We previously reported that this process is driven by the old environment. Here, we found that TAA cells are heterogeneous and contain a progenitor population capable of responding to IL7, expanding, and populating other tissues. This process is entirely dependent on peripheral non-lymphoid tissues, where cells encounter their antigen, leading to their conversion. Most remarkably, we identified old visceral adipose tissue as being enriched with progenitor cells, suggesting that old adipose tissue is a hub for TAA cell generation. We confirmed the role of adipose tissue in TAA development by transplanting old adipose tissue into a young host, demonstrating that this alone is sufficient for the young host's CD8 T cells to acquire the TAA cell phenotype. Overall, our data provides evidence of a systemic age-associated dysregulation of memory CD8 T cells modulated by an old environment and leading to excessive tissue damage during inflammatory responses in old mice.
Language
English (en)
Chair and Committee
Maxim Artyomov
Committee Members
Jonathan Kipnis; Kenneth Murphy; Nathan Singh; Sheila Stewart
Recommended Citation
Shchukina, Irina, "Aging Drives CD8 T Cells to Functional Extremes: From Non-Specific Cytotoxicity to Tissue-Mediated Exhaustion" (2024). Arts & Sciences Electronic Theses and Dissertations. 3270.
https://openscholarship.wustl.edu/art_sci_etds/3270