Programmed Death-1 Inhibition of Phosphatidylinositol 3-Kinase/AKT/Mechanistic Target of Rapamycin Signaling Impairs Sarcoidosis CD4 + T Cell Proliferation

• Published in: American journal of respiratory cell and molecular biology Vol. 56; no. 1; pp. 74 - 82
• Main Authors: Celada, Lindsay J., Rotsinger, Joseph E., Young, Anjuli, Shaginurova, Guzel, Shelton, Debresha, Hawkins, Charlene, Drake, Wonder P.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.01.2017
• Subjects: Adult; Aged; Case-Control Studies; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Demography; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Original Research; Phosphatidylinositol 3-Kinase - metabolism; Programmed Cell Death 1 Receptor - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Sarcoidosis - immunology; Sarcoidosis - metabolism; Sarcoidosis - pathology; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Young Adult; lymphocyte cell-specific protein-tyrosine kinase; AKT; sarcoidosis; programmed death-1; proliferation; phosphatidylinositol 3-kinase
• DOI: 10.1165/rcmb.2016-0037OC
• ISSN: 1044-1549

Patients with progressive sarcoidosis exhibit increased expression of programmed death-1 (PD-1) receptor on their CD4 T cells. Up-regulation of this marker of T cell exhaustion is associated with a reduction in the proliferative response to T cell receptor (TCR) stimulation, a defect that is reversed by PD-1 pathway blockade. Genome-wide association studies and microarray analyses have correlated signaling downstream from the TCR with sarcoidosis disease severity, but the mechanism is not yet known. Reduced phosphatidylinositol 3-kinase (PI3K)/AKT expression inhibits proliferation by inhibiting cell cycle progression. To test the hypothesis that PD-1 expression attenuates TCR-dependent activation of PI3K/AKT activity in progressive systemic sarcoidosis, we analyzed PI3K/AKT/mechanistic target of rapamycin (mTOR) expression at baseline and after PD-1 pathway blockade in CD4 T cells isolated from patients with sarcoidosis and healthy control subjects. We confirmed an increased percentage of PD-1 CD4 T cells and reduced proliferative capacity in patients with sarcoidosis compared with healthy control subjects (P < 0.001). There was a negative correlation with PD-1 expression and proliferative capacity (r = -0.70, P < 0.001). Expression of key mediators of cell cycle progression, including PI3K and AKT, were significantly decreased. Gene and protein expression levels reverted to healthy control levels after PD-1 pathway blockade. Reduction in sarcoidosis CD4 T cell proliferative capacity is secondary to altered expression of key mediators of cell cycle progression, including the PI3K/AKT/mTOR pathway, via PD-1 up-regulation. This supports the concept that PD-1 up-regulation drives the immunologic deficits associated with sarcoidosis severity by inducing signaling aberrancies in key mediators of cell cycle progression.