# Project 2:  T Cell Costimulation: Induction and Regulation of Autoimmunity

> **NIH NIH P01** · HARVARD MEDICAL SCHOOL · 2020 · $617,605

## Abstract

PD-1 synergizes with other co-inhibitory molecules to effectively terminate T cell responses to
control T cell tolerance and tissue inflammation. PD-1 inhibitory signals also contribute to T cell
dysfunction in cancer and chronic infections. A deeper understanding of PD-1 signaling is
needed to determine how to improve pathogen/tumor immunity, while minimizing autoimmunity
and immunopathology. To address these issue, we worked with Core C to generate novel PD-1
signaling domain mutant mice. Mutation of the ITSM motif leads to tumor clearance similar to
PD-1 blockade, but surprisingly, ITSM mutant mice develop lower incidence and reduced
severity of Experimental Autoimmune Encephalomyelitis (EAE). These data suggest that it may
be possible to dissociate beneficial effects of PD-1 pathway blockade on tumor immunity from
autoimmunity. Our findings complement those of P1 showing that ITIM and ITSM mutant mice
have distinct outcomes in chronic viral infection, and P3 showing distinct outcomes of these
strains in cGVHD. Based on these preliminary data, we hypothesize that the PD-1 ITSM and
the ITIM signaling motifs may play distinct roles in different T cell subsets and/or within different
tissue microenvironments. In addition, we have discovered that exhausted CD8+ T cells in
tumors and FoxP3+ Tregs in autoimmune tissue sites highly express a novel inhibitory receptor,
CD112R. P1 has found that CD112R is highly expressed on more terminally exhausted T cells
with distinctive functional properties during chronic viral infection. P3 has identified distinctive
Tregs that highly express CD112R. We hypothesize that CD112R collaborates effectively with
PD-1 to regulate effector T cells and Treg expansion and/or function. To test these hypotheses,
our specific aims are: Aim 1: To assess the cellular and molecular impact of PD-1 ITIM and
ITSM signaling in autoimmunity and anti-tumor immunity. We will use EAE and tumor
models to determine impact of these PD-1 mutations on CD8, CD4 Tcon and FoxP3+ Treg cells
and RNAseq to determine mechanisms by which these mutations affect effector vs. regulatory T
cells responses. Aim 2: Study the cellular and molecular mechanisms by which CD112R
regulates autoimmunity and anti-tumor immunity. We will use novel antibodies and
CD112R-deficient mice to study the roles of CD112R in effector and Treg cells. We will also
investigate if CD112R synergizes or antagonizes PD-1 functions and its differential signaling via
ITIM vs. ITSM motifs. Our studies may help identify strategies to uncouple autoimmunity from
anti-tumor immunity associated with PD-1 blockade, which will have a major impact in patients
treated with check-point blockade therapy.

## Key facts

- **NIH application ID:** 9996461
- **Project number:** 5P01AI056299-17
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Arlene H. Sharpe
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $617,605
- **Award type:** 5
- **Project period:** 2003-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996461

## Citation

> US National Institutes of Health, RePORTER application 9996461, Project 2:  T Cell Costimulation: Induction and Regulation of Autoimmunity (5P01AI056299-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9996461. Licensed CC0.

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