# CD8+ T cell dysfunction promotes sarcoidosis progression

> **NIH NIH K01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $132,891

## Abstract

Project Summary
 Sarcoidosis is an interstitial lung disease (ILD) of unknown etiology with striking disparities in
clinical outcome. About 60% of patients will spontaneously resolve sarcoidosis over time, while
the remainder will experience a gradual decline in lung function as a result of granulomatous
inflammation transitioning to fibrosis. Although the role of CD4+ T cells in pulmonary sarcoidosis
has been appreciated since 1981, the significance of CD8+ T cells has remained undervalued.
Previous investigations have implicated the inhibitory receptor PD-1 as well as the costimulatory
molecule CD28 in pulmonary sarcoidosis progression. Our preliminary findings revealed
elevated frequencies of PD-1-expressing CD8+ T cells in sarcoidosis patients experiencing
disease progression coinciding with functional consequences. PD-1 upregulation impaired the
ability of sarcoidosis CD8+ T cells to proliferate. PD-1 neutralization restored CD8+ T cell
proliferative capacity to healthy control levels. Longitudinal analysis demonstrated increased
PD-1+CD8+ T cells among patients experiencing loss of lung function, but normal PD-1
expression and proliferative capacity in patients with spontaneous resolution. Our results also
demonstrated significantly reduced CD28 expression in PD-1+CD8+ T cells compared to PD-1-
CD8+ T cells. CD28 costimulation is essential for effective T cell immune responses. Loss of
CD28 expression on CD8+ T cells has been shown to promote dermal fibrosis, but the impact of
CD28 deficiency on CD8+ T cells in pulmonary fibrosis remains unknown. This proposal will
identify the signaling mechanisms by which sarcoidosis PD-1+CD8+ T cells promote pulmonary
fibrosis.
 Collectively, these observations support the hypothesis that PD-1 upregulation induces
CD8+ T cell dysfunction through CD28 inactivation which in turn promotes lung fibrosis.
To identify the mechanisms by which PD-1 enhances fibrosis, we propose the following
investigation among sarcoidosis patients with disease resolution, pulmonary disease
progression and healthy controls: Aim 1. To identify the mechanisms by which PD-1-
mediated inhibition of CD28 promotes CD8+ T cell dysfunction. Aim 2. To assess how PD-
1-mediated inhibition of CD28 on CD8+ T cells promotes pulmonary fibrosis in vivo. Aim 2
will be evaluated using the previously published sarcoidosis murine model.

## Key facts

- **NIH application ID:** 9893897
- **Project number:** 5K01HL145338-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Lindsay Johana Celada
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $132,891
- **Award type:** 5
- **Project period:** 2019-03-15 → 2020-08-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893897

## Citation

> US National Institutes of Health, RePORTER application 9893897, CD8+ T cell dysfunction promotes sarcoidosis progression (5K01HL145338-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893897. Licensed CC0.

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