# PSGL-1 mechanisms of T cell exhaustion

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $386,250

## Abstract

Contact PD/PI: Tinoco, Roberto
PROJECT SUMMARY
Diseases leading to antigen persistence as in chronic viral infection and cancer induce development of
exhausted T cells (Texs) that have defective effector function. While Texs represent an altered state of
differentiation in which cells become addicted to antigen for their survival, their functions can be reinvigorated
after inhibitory checkpoint blockade, leading to antigen control in murine, primate, and cancer patients. While
only a small subset of patients responds to checkpoint blockade, many have severe toxicities especially with
checkpoint combination therapy. The fact that clinicians expect most patients to be non-responsive to current
immunotherapies highlights the pressing need to identify, develop, and improve treatments that are efficient
and safe for patients that presently have no treatment options. Our discovery that chronically infected PSGL-1
(P-selectin glycoprotein ligand-1)-deficient mice mounted a robust anti-viral T cell response that supported viral
clearance and was linked to downregulation of multiple inhibitory receptors demonstrates that PSGL-1
represents a new target for immune modulation. Our conclusion is underscored by our finding of enhanced
anti-tumor T cell responses in PSGL-1-deficient mice leading to PD-1 downregulation and tumor control in a
melanoma model. Our findings identified PSGL-1 as a new inhibitory checkpoint that promotes the
development of Texs during chronic viral infection and cancer. Our overall objective in this proposal is to
determine how and when PSGL-1 signaling inhibits T cells during chronic antigen stimulation. Our central
hypothesis is that PSGL-1 signaling modulates inhibitory mechanisms not only in T cells but also in other
immune cells that contribute to T cell exhaustion. The rationale is that once we fully understand this pathway,
we can develop effective therapeutics targeting PSGL-1 to reinvigorate Texs. The proposed research will
provide a mechanistic analysis of when, where, and how the PSGL-1 inhibitory signaling pathway mediates
Texs development. We will test our hypothesis by pursuing the following three specific aims 1) To determine
the cellular and temporal requirement for PSGL-1 mediated T cell exhaustion 2) To determine the therapeutic
potential of relieving PSGL-1 inhibition and 3) To identify molecular mechanisms by which PSGL-1 mediates
inhibitory pathways in T cells. This contribution will be significant because understanding how this inhibitory
checkpoint axis fundamentally functions has the potential to lead to the development of new therapeutic
interventions targeting a new class of inhibitory receptors to modulate immune responses and help prevent and
treat a wide range of diseases. Our studies are innovative as they may expand the development of a new class
of drugs targeting adhesion receptor inhibitory pathways to reverse T cell exhaustion. Understanding the
mechanisms by which PSGL-1 mediates inhibitory signals ...

## Key facts

- **NIH application ID:** 10356040
- **Project number:** 5R01AI137239-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Roberto Tinoco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2019-01-17 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356040

## Citation

> US National Institutes of Health, RePORTER application 10356040, PSGL-1 mechanisms of T cell exhaustion (5R01AI137239-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10356040. Licensed CC0.

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