The PD-1:PD-L immunoregulatory pathway has major roles in controlling exhausted/dysfunctional T cells and this pathway has become a major clinical target in cancer and chronic infection. The role of this pathway in acute infections is unclear. Available data are conflicting, but have focused on effector CD8 T cell expansion. Our new exciting preliminary data identify a novel and major role for the PD-1:PD-L pathway as a key integrator of signals that result in optimal CD8 T cell memory quality. Specifically, we have found that the PD-1 pathway shapes effector and memory CD8 T cell differentiation during acute influenza (Flu) infection. These findings give impetus to investigating how PD-1 and its ligands control CD8 T cell differentiation following acute infections. Thus, we will define mechanisms by which the PD-1 pathway regulates effector CD8 T cell differentiation and development of memory CD8 T cells during Flu infection. There is a tremendous need for new or improved vaccines against respiratory pathogens such as Flu. However, it has been challenging to harness the potential of T cell-based vaccines for respiratory viral infections partly due to limited knowledge of how to effectively induce the most protective types of memory T cells. Determining how PD-1 promotes CD8 T cell memory may generate a better understanding of protective immunity to Flu and enable novel vaccine strategies for other respiratory viruses. In Project 2 we will interrogate where and when PD-1 pathway signals are important for effector and memory CD8 T cell development, which interactions within the PD-1 pathway are involved and which APCs deliver these signals, and how these events are integrated with the downstream transcription factors T-bet and Eomes. We will test the hypothesis that, rather than simply inhibiting responses, the PD-1:PD-L pathway acts as a rheostat regulating cell fate decisions of CD8 T cells and long-term immunity to acute viral infection. We will test this hypothesis through the following Aims:
Aim 1 : To test the hypothesis that the PD-1 pathway regulates early T cell activation dynamics during priming.
Aim 2 : To test the hypothesis that the PD-1 pathway regulates effector CD8 T cell differentiation and function after priming, and define when and where this regulation occurs.
Aim 3 : To test the hypothesis that the PD-1 pathway affects CD8 T cell memory via altering homeostasis and regulating novel memory T cell subsets and Eomes. Studies in P2 will synergize with those in P1 and P3 given a major interest in P1 and P2 on subsets of memory CD8 T cells and the role of T-bet. P1, P2 and P3 also have a strong interest sin homing and migration as well as the PD-1 pathway creating a common set of shared themes. Finally, key studies on early priming events and homing and migration will be enabled through Core B.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-BDP-I (M1))
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Harvard Medical School
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