It has been shown that aging significantly impact the T cell receptor repertoire. It is also known that CMV infection has a profound impact on the immune system's composition and function, especially with respect to CD8+ T cells. Study in mice showed that chronic bystander infection impairs the CD8+ T cell repertoire on both transition from effector to memory T cells as well as the function of preformed memory CD8+ cells. However, whether these occurs in humans that have a much larger T cell repertoire and more resistant to thymic output decrease is not known. In addition, it is not known how aging and CMV infection impact the maintenance and function of precursor T cells that may protect host from future infections. Further we showed that aging reduces the frequency of high-affinity T cell in nave precursor T cells. However, studying these in human is challenging, especially if we would like to survey the landscape of antigen-specific T cells to all possible peptide epitope bound to one type of HLA as a way to assess the completeness, functional competence, and the affinity distribution of the T cells to all possible antigens for one protein or an organism. Thus, in the proposed study, we will integrate several tools we recently developed to assess T cells from multiple angles, namely TetATCR-Seq for linking of TCR sequences to hundreds of pMHC antigens at single cell level in a high-throughput manner, high-throughput CytoSeq that interrogates the expression level of 400 genes in each of 50,000 single cells, and iTAST that measure T cell receptor. We will use these tools in combination of a human tetanus, diphtheria, and pertussis vaccine recall study to comprehensively study the completeness, functional competence, and the affinity distribution of the precursor T cells to all possible HCV virus peptides and memory T cells to all possible tetanus and diphtheria toxin peptides. Expected results will systematically evaluate the impact of aging and CMV infection on the maintenance and function of antigen-specific precursor and memory T cells.

Public Health Relevance

Aging and CMV infection correlate with a dysfunctional or inadequate immune response. With the population in the US and other industrialized countries shifting towards a greater fraction of older people, this becomes an ever more urgent issue. Data generated from this study will help us understand how aging and CMV infection impact the CD8+ T cell repertoire, which will provide scientific evidence in policy making regarding CMV vaccine development and immunization.

National Institute of Health (NIH)
National Institute on Aging (NIA)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZAI1)
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Fuldner, Rebecca A
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University of Texas Austin
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
United States
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