The development of optimal T cell memory is the goal for many vaccination strategies for infectious disease. Yet the process of memory T cell differentiation and the factors that influence memory T cell quality remain poorly understood. Recent studies have highlighted a key role for inflammatory signals in regulating memory T cell differentiation with evidence indicating that inflammation can be beneficial for T cell priming, but can also induce terminal differentiation of effector T cells. Inflammation is a key feature of most infections, but it is unclear if the effects of unrelated infections can influence T cells of a different specificity in a setting of co-infection. Co-infection can have a negative effect on immunity to unrelated pathogens, but the immunological mechanisms for this effect are not known. In preliminary studies we have found that two types of chronic infections inhibit optimal generation of CD8 T cell memory to unrelated antigens. This effect was not due to persisting antigen since the specificity of the memory CD8 T cells examined was unrelated to the persisting infections. Thus, we hypothesize that the inflammatory environment of chronic infections can negatively impact the pattern of memory T cell differentiation. In this proposal we will test this hypothesis by examining the impact of the inflammatory environment on different subpopulations of effector and memory CD8 T cells and defining the molecular mechanisms for this effect. We will: 1) Determine which stages of memory CD8 T cell development are impacted by co-infection;2) Define the pathways that regulate memory differentiation during co-infection;and 3) Define the transcriptional pathways controlling arrested memory T cell differentiation due to chronic co-infection. A better understanding of the impact of chronic co-infections on memory T cell differentiation is needed to help optimize antiviral vaccines. Our goal in this project is to begin to address these questions and investigate how bystander chronic infections shape antiviral memory T cell differentiation.

Public Health Relevance

More than 2 billion people worldwide are infected with HIV, HCV, HBV, malaria TB and neglected tropical diseases. These same populations would benefit the most from improved vaccines. It is clear that chronic infections can impact immunity to unrelated antigens, but the immunological basis for this effect is unclear. Our goal is to define how unrelated infections impact immunological memory in hopes to improve vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BDP-I)
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University of Pennsylvania
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