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 CD41 T cells. Upregulation 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 1 T cells isolated from patients with sarcoidosis and healthy control subjects. We confirmed an increased percentage of PD-1 1 CD4 1 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 = 20.70, 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 CD41 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.

Nivolumab-related cutaneous sarcoidosis in a patient with lung adenocarcinoma

“…However, an overly simplistic paradigm may be inaccurate because there is also paradoxical evidence of PD-1's role in sarcoidosis. A recent study found that PD-1 was upregulated on CD4 + T cells in sarcoidosis patients compared with healthy controls 8 . The authors posit that PD-1 overexpression may decrease T-cell proliferative capacities leading to the immunologic derangements associated with sarcoidosis.…”

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

“…In melanoma cells, STAT3 transcription has been shown to be negatively regulated by phosphatidylinositol 3-kinase (PI3K) (36). This pathway may have particular relevance to PD-1 manipulation of STAT3 in sarcoidosis subjects due a recent report demonstrating the capacity of PD-1 to inhibit PI3K expression in sarcoidosis CD4 + T cells (37). It is possible that PD-1 indirectly regulates STAT3 transcription through inhibition of PI3K, resulting in increased STAT3.…”

Etiology and Immunopathogenesis of Sarcoidosis: Novel Insights

“…Sarcoidosis CD4þ T cells have increased PD-1 expression and reduced proliferation capacity, which was restored upon blockage of the PD-1 pathway. 46,47 In addition, patients with resolving disease were found to have reduced PD-1 expressing CD4þ T cells and normal proliferative capacity compared with the patients with progressive disease. 48 P13K and Akt are part of the signaling pathway that is critical for cell proliferation.…”

“…In response to foreign antigens, T cells undergo proliferation and differentiation to facilitate antigen clearance, and loss of T-cell proliferation might therefore lead to antigen persistence. Impaired T-cell proliferation possibly leads to disease progression in some sarcoidosis cases, 47 as sarcoidosis might be caused by an intracellular infection in which the cellular immune response is the most important defense mechanism. Those studies indicate that blocking PD-1 pathways could be a new therapeutic option in sarcoidosis patients.…”