Anti-microbial T cell responses play a major role in determining the outcome of infection. Chronic infections are often distinguished by T cell responses that are not able to fully eliminate the pathogen. The mechanisms that explain this failure of T cell effector responses are only beginning to be understood. During the current funding period, we have used the lymphocytic choriomeningitis virus (LCMV) model to investigate how the PD-1 pathway regulates T cell responses during chronic infection. We have found that the PD-1 pathway has multifaceted roles in protective immunity. We discovered that in addition to PD-L1, PD-L2 limits responses of exhausted T cells. We also have shown that PD-L1 has distinct roles on hematopoietic and non- hematopoetic cells during chronic infection. However, we lack a mechanistic understanding of PD-L1 and PD-L2 functions on specific cell types. A major goal of this proposal is to elucidate mechanisms by which PD-1 and its ligands regulate CD8 T cell exhaustion, issues of fundamental and translational importance, given the therapeutic promise of this pathway. In addition, we have discovered a new function for the PD-1 pathway in protective immunity. We have identified a role for PD-1 in regulating humoral immunity by inhibiting the generation and function of T follicular regulatory cells. Thus, we will not only address how the PD-1 pathway regulates CD8 T cell exhaustion, but also how it controls humoral immunity. In addition, we will study roles of two novel coinhibitory molecules identified by PPG investigators in anti-microbial immunity: repulsion guidance molecule b (RGMb) and protein C receptor (PROCR). Dr. Freeman (Core B) identified RGMb as a second binding partner for PD-L2. The rescue of T cell exhaustion in PD-L2 deficient mice leads us to study RGMb function during chronic infection. Dr. Kuchroo (PI, Project 3) has identified protein C receptor (PROCR) as a novel coinhibitory molecule;in collaboration we have found that PROCR is highly expressed on exhausted CD8 T cells. We will study if PROCR regulates T cell exhaustion. Our main hypothesis is that PD-1 pathway members and PROCR regulate protective immunity during acute and chronic infections. To test this hypothesis, our Specific Aims are to: 1) Analyze how PD-1 and its ligands regulate humoral immunity during acute mucosal/localized viral infection (influenza) versus systemic infection (LCMV). 2) Investigate roles of the PD-1 and PROCR pathways in controlling exhausted CD8 T cells during chronic LCMV infection. Our goals are to determine how to optimally modulate the PD-1 and PROCR pathways therapeutically in chronic infection, and develop new strategies to promote protective immunity during acute viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI056299-11
Application #
8742091
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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