# T Cell Immunity in Giant Cell Arteritis

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $581,040

## Abstract

Project Summary
Giant Cell Arteritis (GCA) is a granulomatous vasculitis of the aorta and its major branch vessels that
causes blindness, stroke and aortic aneurysm and serves as an informative model system of immune-mediated
vaso-occlusive disease. Previous work supported by this award has implicated the spontaneous failure of the
PD1/PD-L1 immune checkpoint in driving excessive T cell immunity that manifests as autoimmune disease of
the three-layered large elastic arteries.
Recent work has extended the immune checkpoint deficiencies in GCA patients to the inhibitory CD155/CD96
checkpoint, raising the intriguing possibility that a common abnormality in inhibitory signaling unleashes
autoimmunity in blood vessels. We found that macrophages (Mφ) from GCA patients lacked surface expression
of the inhibitory checkpoint ligands CD155 and PD-L1, enabling the unopposed expansion of pathogenic CD4+
T cells. Lack of negative signals delivered by CD155low Mφ licensed CD4+CD96+ T cells to become tissue
invasive and differentiate into IL-9 producing effector cells. Gain-of function and loss-of-function experiments
identified IL9 as a key regulator in vessel wall inflammation, linking the breach of self-tolerance to the CD155-
CD96-IL9 pathway. In subcellular mapping studies of GCA Mφ, the CD155 and PD-L1 protein were retained on
the membranes of the endoplasmic reticulum (ER) and ER stress induced retention of the ligands, providing
important clues towards the underlying molecular abnormalities. These data strongly support a “lost inhibition
model” as the core abnormality in GCA.
Here, we propose that GCA is a syndrome of immune checkpoint failure, and that vascular inflammation
is a result of insufficient containment of antigen-reactive immune responses. Our data assign the
primary defect to antigen-presenting cells which retain inhibitory checkpoint ligands in the ER.
Unrestrained CD4+ T cells invade the vessel wall and misdifferentiate into vasculitogenic effector cells.
To pursue this hypothesis, we will define molecular and functional abnormalities in CD155low PD-L1low Mφ;
investigate the impact of ER stress on the Mφ transcriptome and proteome and map the molecular defects
causing disruption of CD155 intracellular trafficking (Aim 1). Aim 2 will examine the impact of CD155low PD-
L1low Mφ on T cell differentiation and functional commitment. Specifically, we will identify CD4+ T cell populations
that escape from containment in the absence of CD155 and PD-L1 signaling, define their phenotypic and
functional specification through CITE-Seq and examine their disease relevance in the human artery-NSG model
system of GCA. This proposal aims to leverage understanding of inhibitory immune checkpoints to build new
paradigms for the diagnosis and therapy of autoimmune vascular inflammation.

## Key facts

- **NIH application ID:** 10823778
- **Project number:** 2R01HL142068-05
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Cornelia M. Weyand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $581,040
- **Award type:** 2
- **Project period:** 2018-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823778

## Citation

> US National Institutes of Health, RePORTER application 10823778, T Cell Immunity in Giant Cell Arteritis (2R01HL142068-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10823778. Licensed CC0.

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