T cell immunity plays 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 LCMV model to investigate how the PD-1 pathway regulates T cell responses during acute and chronic infection. We have discovered that the PD-1+ stem-like population is responsible for the dramatic expansion of CD8+ T cells after PD-1 pathway. In addition, we identified roles of the PD-1 pathway in regulating CD8 and humoral responses during acute viral infection. However, the mechanisms of PD-1 signaling and its blockade are still not well understood. A deeper understanding of PD-1 signaling is needed to determine how to improve anti-viral immunity, while minimizing autoimmunity and immunopathology. To address this issue, we worked with Core C to generate novel PD-1 signaling domain mutant mice. We have found that both the PD-1 ITIM and ITSM motifs mediate PD-1 signaling in vivo. Notably, our data suggest the possibility to dissociate beneficial effects of PD-1 pathway blockade on viral immunity from immunopathology. Our findings complement those of Project 2 showing that ITIM and ITSM mutant mice have distinct outcomes in cancer and autoimmunity models, and Project 3 showing distinct outcomes in transplantation. Based on these data, we hypothesize that the PD-1 ITIM and ITSM motifs have distinct and overlapping functions, and that cell type and disease context will dictate which signaling motif is critical for controlling different aspects of the PD-1 inhibitory signal. In addition, we have discovered that the inhibitory receptors CD101 and CD112R are highly expressed on more terminally exhausted T cells with distinctive functional properties during chronic viral infection. Projects 2 and 3 have identified distinctive Tregs that highly express CD112R and CD101. Our findings lead us to hypothesize that CD101 and CD112R may serve as additional brakes on CD8 T cells in chronic infection, reducing their ability to respond to PD-1 blockade. To test these hypotheses, our Specific Aims are to 1) investigate roles of the PD-1 ITIM and ITSM motifs in controlling protective immunity versus immunopathology during acute and chronic viral infection; and 2) identify roles of CD101 and CD112R in controlling T cell exhaustion. Our goals are to elucidate mechanisms by which PD-1 regulates T cell exhaustion, identify new strategies for combination therapies to enhance T cell immunity during chronic viral infection, as well as new strategies to augment protective immunity during acute infections.

Public Health Relevance

Chronic viral infections cause significant morbidity and mortality, and T cell dysfunction is a major reason for failure of viral control during chronic infections. Identifying new strategies for combination therapies to treat chronic viral infections and augment acute infections will greatly improve global health.

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)
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Harvard Medical School
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