# T Cell Immunity in Giant Cell Arteritis

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2021 · $354,759

## Abstract

Project Summary
Giant cell arteritis (GCA) is a vision-threatening vasculitis that causes ocular ischemia due to occlusion of
critical arteries supplying the optic nerve, the retina, the iris, or other orbital structures. The typical presentation
of vision loss in GCA is arteritic anterior ischemic optic neuropathy (AION) or central retinal artery occlusion,
with a high risk for progression to the second eye. Blindness is preventable if the disease is diagnosed and
treated promptly. GCA patients have hyperreactive CD4 T cells that invade into the wall layers of arteries
where together with macrophages they induce lumen-occlusive intimal hyperplasia. The defect driving CD4 T
cell hyperreactivity is not understood. The current application will examine the hypothesis that CD4 T cells
from GCA patients fail to activate the immuno-protective Programmed cell death protein 1 (PD-1)
checkpoint. Upon binding its ligand Programmed death-ligand 1 (PD-L1), the PD-1 receptor transmits a STOP
signal to inhibit T cell effector functions. The proposal builds on preliminary studies demonstrating low
expression of the PD-L1 immuno-inhibitory ligand on dendritic cells (DC) and endothelial cells (EC) from GCA
patients. Also, blockade of the PD-1 immune checkpoint in chimeric mice carrying human arteries and GCA
CD4 T cells results in marked exacerbation of vasculitis, induces endothelial-mesenchymal transition and
aggravates intimal layer outgrowth. Experiments designed in this proposal rely on a series of enabling
resources, specifically on a large cohort of GCA patients, a biobank of GCA-affected temporal arteries and a
chimera system in which vasculitis is induced in human arteries engrafted into immune-deficient mice.
 Specific Aim 1 examines on a mechanistic level how PD-L1low dendritic cells affect the duration, the
amplitude and the quality of vasculitogenic immune responses. Experiments have been designed to
understand how insufficient expression of PD-L1 modulates T cell activation, expansion, tissue invasion,
survival and cytokine production. Specific Aim 2 investigates how PD-L1 expression on adventitial
microvascular endothelial cells (MVEC) shields the vessel wall from immune attack and protects vascular
barrier function. In vitro and in vivo, we will define how MVEC-derived negative signals modulate the behavior
and effector functions of PD-1+ CD4 T cells and how endothelial PD-L1 deficiency promotes vasculitogenic T
cells. Specific Aim 3 will identify mechanisms leading to insufficient PD-L1 expression on GCA DC, with the
goal to repair the defective immune checkpoint. By screening the responsiveness of GCA and control DC to
stimuli and signaling pathway inhibitors, we have discovered the IFN-γ-BMP4-pSMAD1/5-IRF1 module as a
critical regulator of PD-L1 expression. Patient-derived DC display IFN-γinsensitivity and fail to upregulate
canonical bone morphogenetic protein (BMP4) signaling. We will probe the functionality of the BMP4-
pSMAD1/5-IRF1 signal...

## Key facts

- **NIH application ID:** 10457645
- **Project number:** 7R01HL142068-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Cornelia M. Weyand
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $354,759
- **Award type:** 7
- **Project period:** 2018-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457645

## Citation

> US National Institutes of Health, RePORTER application 10457645, T Cell Immunity in Giant Cell Arteritis (7R01HL142068-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10457645. Licensed CC0.

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