Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Hildegund C. Ertl

Second Advisor

Scott E. Hensley

Abstract

There is a vital need for better vaccines for the aging population, and especially better vaccines to influenza viruses. To address this, I studied immunosenescence in B cells and antibody secreting cells (ASCs) in mice and humans. In humans, I measured humoral immune responses to the trivalent inactivated influenza vaccine (TIV) during the 2011-12 and 2012-13 influenza seasons. ASCs in the aged were observed to have decreased expression of the defining markers CD27 and CD38. Aged ASCs also expressed lower levels of B and T Lymphocyte attenuator (BTLA) on their surface. Expression of BTLA inversely correlated with age and appeared to be linked to shifting the nature of the response from IgM to IgG. High BTLA expression on mature B cells was linked to higher IgG responses to the H1N1 virus. Finally, high BTLA expression on isotype switched memory B cells was linked to better preservation of virus neutralizing antibody titers and improved recall responses to influenza vaccination given the following year. In mice, aged ASCs expressed high levels of PD-1 and this correlated with high levels of cellular reactive oxygen species (cROS), indicating a link between immunoregulator expression and metabolism. Micro-array studies of bone marrow-derived ASCs showed substantial differences in their gene expression profile in aged as compared to young mice, which may explain their deteriorating functions. In summary, expression levels of immunoregulators on ASCs or their precursor populations change upon aging. Aged ASCs or their precursors are metabolically different from their younger counterparts, and these two factors are linked.

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