2008 AFAR Research Grant: Role of Programmed Death Receptor-1 on Aging CD4+ T cells

Please give a brief summary of your AFAR research project.
Yearly outbreaks of influenza have more consequential effects on individuals over the age of 65, largely attributable to the defects in their immune cell types. Since, elderly individuals over the age of 70 represent the fastest major users of United States health care resources, it is critical to understand the cause of defects in lymphoid populations as it might lead to the development of new strategies to enhance vaccine efficacy for this particular group. Negative co-receptors like CTLA-4, BTLA, NKG2a and PD-1 expressed on T lymphocytes significantly down-regulate T cell functions when interact with their respective ligands. Our preliminary data shows that there is a dramatic increase in the proportion of PD-1 expressing CD4+ T cells in the uninfected aged but not young mice. We hypothesize that PD-1 expression on old CD4+ T cells make them dysfunctional in the aged animals. Using mouse model of respiratory influenza virus A infection, we will address if in vivo blocking of PD-1 interaction with its respective ligand PDL1 can direct the generation of functionally competent flu-specific memory CD8+ T and B cell pool and effectively reduce viral load in the lung tissue. We believe the results obtained from these studies might lead to the development of new strategies to enhance vaccine efficacy for elderly individuals.

What problems are you addressing and what specific questions will your research seek to answer?
We are trying to understand the factors that are responsible for age-related defects in CD4 T cell function. Our preliminary observation in the mouse model suggest that there is a dramatic increase in the proportion of programmed death receptor-1 (PD-1) molecule expressing CD4+ T cells in uninfected aged animals. We hypothesize that PD-1 interaction with its respective ligand PDL1 causes T cell dysfunction in aged host and will explore if in vivo blocking of PD-1 interaction can augment T and B cell immunity to influenza virus, an infection that has more consequential effects in the elderly individuals.

What aspects of your project are most interesting from a scientific point of view?
We made the observation that there is a dramatic increase in the proportion of PD-1 expressing CD4+ T cells with advancing age. Previously, it was shown in chronic viral infections that PD-1 expression on viral antigen specific CD8+ T cells make them dysfunctional and blocking of PD-1 interaction can rejuvenate their functional status. We hypothesize that PD-1 expression on old CD4+ T cells is associated with age-related defects in the function of CD4+ T cells and in vivo blocking of PD-1 interaction can augment old T cell function. We will be testing our hypothesis in aged mouse model of respiratory influenza virus A infection. The results obtained from these studies might lead to the development of new strategies to enhance vaccine efficacy for elderly individuals.

What are the implications of your research for age-related diseases and disorders?
The results obtained from these studies might lead to the development of new strategies to enhance vaccine efficacy for elderly individuals.

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