title: Programmed Death-1 Inhibition of Phosphatidylinositol 3-Kinase/AKT/Mechanistic Target of Rapamycin Signaling Impairs Sarcoidosis CD4+T Cell Proliferation.
abstract: 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.
authors: 1 Division of Infectious Diseases, Department of Medicine, and.|2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors: Lindsay J
authors: LJ
authors: Celada
authors: 1 Division of Infectious Diseases, Department of Medicine, and.
authors: Joseph E
authors: JE
authors: Rotsinger
authors: 1 Division of Infectious Diseases, Department of Medicine, and.
authors: Anjuli
authors: A
authors: Young
authors: 2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors: Guzel
authors: G
authors: Shaginurova
authors: 1 Division of Infectious Diseases, Department of Medicine, and.
authors: Debresha
authors: D
authors: Shelton
authors: 1 Division of Infectious Diseases, Department of Medicine, and.
authors: Charlene
authors: C
authors: Hawkins
authors: 1 Division of Infectious Diseases, Department of Medicine, and.|2 Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors: Wonder P
authors: WP
authors: Drake
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D003710:Demography; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012507:Sarcoidosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D055815:Young Adult
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: AKT; lymphocyte cell-specific protein-tyrosine kinase; phosphatidylinositol 3-kinase; programmed death-1; proliferation; sarcoidosis