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Theses Doctoral

The effect of aging on human T cell subset compartmentalization and maintenance in tissue sites

Thome, Joseph John-Charles

Knowledge of human T cell responses and the pathways for their differentiation and maintenance from development into adulthood remains largely sparse. Much of what is known concerning the adaptive immune response in humans derives from analysis of peripheral blood, even though the majority of T cells within the body reside in tissue sites. We have established a protocol with LiveOnNY, the organ procurement organization of the New York metropolitan area allowing us access to healthy tissues from individual organ donors of a diverse background. Through novel analysis of lymphoid and mucosal tissues from infant and adult organ donors, we reveal how naïve, regulatory, and memory T cells dynamically populate and are maintained in tissues and circulation over the human lifespan.
An initial multidimensional, quantitative analysis of human T cell compartmentalization involving 56 organ donors of a broad age range revealed that distribution of naïve, effector, and memory T cell subsets is largely dependent on tissue localization and differentiation state. Furthermore, T cell homeostasis driven by cytokine or TCR-mediated signals is dependent on CD4+or CD8+ T cell subset. Examining whether T cell subset distribution was set at birth, we compared T cell populations from a cohort of pediatric organ donors in the first two years of life to tissues from young adult donors aged 15-25 years. Results show a dynamic compartmentalization of naïve and regulatory T cells in all tissues early in life that is rapidly replaced with effector memory T cells (TEM) especially in mucosal sites further revealing the importance of a local adaptive immune response. Interestingly, the proportion and distribution of these T cell populations in tissue sites show varying levels of reliance on thymic output.
Further evidence for the compartmentalization of the adaptive immune response and mechanisms for T cell maintenance throughout life can be shown through the analysis of T cell receptor sequences. We examined naïve and TEM populations in lymph nodes and spleen as a function of thymic output revealing low sharing of the naïve T cell repertoire between tissue sites with higher amounts of overlapping clones seen in TEM populations, especially with CD8+ T cells. These differences highlight potentially different roles for CD4+ and CD8+ T cells in the response to pathogen and their maintenance with age.

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More About This Work

Academic Units
Microbiology, Immunology, and Infection
Thesis Advisors
Farber, Donna L.
Degree
Ph.D., Columbia University
Published Here
March 8, 2016
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