T cell immunity is crucial for human survival, coordinating responses to new pathogens and establishing immune memory in early life, and, in later life, maintaining immune homeostasis through immune and tumor surveillance. A lifetime of exposure to diverse antigens through infections and vaccination generate memory T cells that can persist for decades in the absence of antigenic re-exposure and comprise the predominant T cell subset throughout adult life.
These memory T cells are susceptible to repeated stimulation over time due to chronic infections, and with age, T cells undergo dynamic alterations that are associated with immunodeficiency. Studies of memory T cell persistence and aging mostly sample peripheral blood while the majority of T cells, particularly tissue-resident memory T cells (TRM), are maintained in diverse tissues, including lymphoid and mucosal sites, where they mediate frontline protection. The longevity, maintenance, and age-associated changes of T cells across these key sites remain unknown and are important for developing age-targeted strategies for immune modulation.
Utilizing our human tissue resource through a collaboration with LiveOnNY, a local organ procurement organization, we presented a comprehensive analysis of human T cell subset dynamics and aging in blood and tissue samples obtained from 88 organ donors over 10 decades of life. We revealed that T cell tissue localization and subset are factors that influence the phenotypic, functional, and epigenetic changes observed over age. Using retrospective radiocarbon (14C) birth dating and assessment of cellular turnover, we showed that T cells across blood and tissues are maintained through continuous turnover.
However, within tissues, histological and flow cytometric analyses demonstrated age-associated structural changes, regression, and senescence in lymphoid but not in mucosal organs. We observed differential expression of proliferation marker Ki67 and senescence markers between T cell subsets, with CD8+ TRM having the lowest expression of these markers compared to circulating TEM and TEMRA, suggesting that TRM may undergo less turnover for their maintenance. Epigenetic analysis revealed comparable age-associated loss in global DNA methylation for CD8+ TEM and TRM cells but increased epigenetic regulation of gene expression over age for TRM cells. Paired with transcriptomic analysis, we observed inverse correlation between promoter DNA methylation and gene expression at genes related to T cell differentiation, homing, survival, regulation, and effector function, predominantly in TRM.
Our results provide compelling evidence for continuous turnover for T cells across the body but different aging phenotypes depending on tissue localization and/or T cell subset, with tissue residency potentially protecting T cells from senescent changes over age, and these findings may have implications in the design of effective age-targeted treatment and prevention strategies.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/8jva-by66 |
| Date | January 2024 |
| Creators | Lam, Nora |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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