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.
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.
