# Project 1:  Co-stimulation and Regulation of Anti-viral Immunity

> **NIH NIH P01** · HARVARD MEDICAL SCHOOL · 2022 · $660,826

## Abstract

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.

## Key facts

- **NIH application ID:** 10470787
- **Project number:** 5P01AI056299-19
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Arlene H. Sharpe
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $660,826
- **Award type:** 5
- **Project period:** 2003-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470787

## Citation

> US National Institutes of Health, RePORTER application 10470787, Project 1:  Co-stimulation and Regulation of Anti-viral Immunity (5P01AI056299-19). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470787. Licensed CC0.

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