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.
Sarcoidosis is an interstitial lung disease (ILD) of unknown cause, with limited treatment options that are associated with significant side effects. It is a granulomatous disorder in which some patients will spontaneously resolve their disease over time, while others show a progressive decline in lung function. A significant contributor to the loss of lung function is the development of fibrosis; therefore, this is a proposal to identify how increased expression of the inhibitory receptor PD-1 on CD8+ T cells promotes pulmonary fibrosis in sarcoidosis patients.
