Date of Graduation

12-2015

Document Type

Dissertation (PhD)

Program Affiliation

Epigenetics and Molecular Carcinogenesis

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Ellen Richie, PhD`

Committee Member

Shawn Bratton, PhD

Committee Member

David Johnson, PhD

Committee Member

Kevin McBride, PhD

Committee Member

Jagan Sastry, PhD

Abstract

The thymus maintains T cell receptor (TCR) repertoire diversity through perpetual release of self-MHC restricted naive T cells. However, thymus involution during the aging process reduces naïve T cell output, leading to defective immune responsiveness to newly encountered antigens. We have found that early thymus involution precipitates the age-associated shift favoring memory T cell dominancy in young control mice. Furthermore, we have shown that age-related thymus involution is prevented in mice expressing a keratin 5 promoter-driven Cyclin D1 (K5.D1) transgene in thymic epithelial cells (TECs). Thymopoiesis occurs normally in K5.D1 transgenic thymi and sustains T cell output to prevent the age-associated decline of naïve T cells in the periphery. We find that K5.D1 recent thymic emigrants (RTEs) undergo typical phenotypic maturation. In addition, functional studies show that K5.D1 peripheral T cells are responsive to anti-CD3 and anti-CD28 stimulation in vitro. Competitive adoptive transfer studies with K5.D1 and nontransgenic RTEs indicate that K5.D1 RTEs are incorporated into the peripheral T cell pool comparably to nontransgenic controls. However, K5.D1 mature naïve (MN) T cells out-persist control counterparts, which likely occurs, in part, to increased expression of the cytokine receptor IL-7Rα. Collectively, these data show that preventing thymus involution not only sustains T cell output to maintain naïve T cell numbers, but also provides functionally competent MN T cells during aging.

Keywords

Recent thymic emigrant, mature naive T cells, Cyclin D1, thymocyte development, peripheral T cells

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