Author ORCID Identifier

https://orcid.org/0000-0003-4024-4977

Date Available

6-27-2024

Year of Publication

2023

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

First Advisor

Dr. Marlene Starr

Abstract

Chronic systemic inflammation, known as inflammaging is considered a hallmark of aging and associated diseases. While adipose tissue has long been considered only as a caloric reservoir regulating systemic energy homeostasis, research in the past couple of decades substantiate its endocrine function to secrete an array of inflammatory mediators and hormones, which have physiological effects on multiple organ systems, and contribute to inflammaging. Redistribution of adipose tissue from subcutaneous to visceral depots, changes in the immune profile and the chronic inflammatory state are among the major sources of adipose tissue dysfunction with aging.

This dissertation is focused on identifying and characterizing a unique population of T cells, called γδ T cells, in visceral adipose tissue (VAT) with aging. My studies identified an age-associated increase in γδ T cell numbers in VAT and a progressive trend of accumulation of these cells over the lifespan in C57BL/6J mice. Importantly, this accumulation is also consistent in humans. I explored the role of VAT resident γδ T cells in inflammation using a genetic deletion model that lacks γδ T cells (TCRδKO) and showed that lack of γδ T cells results in reduced inflammation both locally and systemically. The potential for γδ T cells to promote inflammation with aging set the stage to understand the maintenance of this population in VAT and the mechanisms for the age-associated accumulation. I evaluated several physiological mechanisms that may contribute to γδ T cells accumulation. Using isochronic parabiotic pairs of wild-type (WT) and TCRδKO mice at young and old age, I found minimal recruitment of peripheral γδ T cells into VAT without a significant change by aging, suggesting a minor contribution of migration to γδ T cell accumulation with aging. Since the number of T cells are tightly regulated within a tissue to maintain homeostasis, I further evaluated two potential driving forces, proliferation, and programmed cell death as mechanisms to increase the number of γδ T cells in VAT with aging. Studies using Ki67 as a proliferation marker and in vivo EdU incorporation demonstrated that the absolute number of proliferating γδ T cells per gram of VAT significantly increased in the aged VAT compared to young and middle age, indicating that an increase in the local proliferating γδ T cell population contributes to the age-associated accumulation. Analysis of apoptosis via caspase activity, revealed a decrease in apoptosis in γδ T cells with a concomitant increase in the live population among the middle-aged group of mice that continued into the aged. Comparative studies in peripheral lymph nodes showed the expected increase in apoptosis among the aged, suggesting that γδ T cells are protected from age-associated apoptosis specifically in VAT. Changes in VAT microenvironment with age that led to a reduction in apoptosis will be an interesting avenue for future research. Collectively, these data suggest that an increased number of tissue-resident proliferating γδ T cells and increased survival of γδ T cell populations, rather than peripheral migration, account for the age-associated γδ T cell accumulation observed in VAT. These findings are important to better understand how adipose tissue dysfunction and related changes in its immune profile contribute to inflammaging among the elderly.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2023.280

Funding Information

This study was supported by the National Institute of General Medical Sciences Grant (no.:R01 GM129532) and National Institute of Aging Grant (no.: R56 AG061508).

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