The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands

AL Kinter, EJ Godbout, JP McNally, I Sereti… - The Journal of …, 2008 - journals.aai.org
AL Kinter, EJ Godbout, JP McNally, I Sereti, GA Roby, MA O'Shea, AS Fauci
The Journal of Immunology, 2008journals.aai.org
Abstract The programmed death (PD)-1 molecule and its ligands (PD-L1 and PD-L2),
negative regulatory members of the B7 family, play an important role in peripheral tolerance.
Previous studies have demonstrated that PD-1 is up-regulated on T cells following TCR-
mediated activation; however, little is known regarding PD-1 and Ag-independent, cytokine-
induced T cell activation. The common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21,
which play an important role in peripheral T cell expansion and survival, were found to up …
Abstract
The programmed death (PD)-1 molecule and its ligands (PD-L1 and PD-L2), negative regulatory members of the B7 family, play an important role in peripheral tolerance. Previous studies have demonstrated that PD-1 is up-regulated on T cells following TCR-mediated activation; however, little is known regarding PD-1 and Ag-independent, cytokine-induced T cell activation. The common γ-chain (γc) cytokines IL-2, IL-7, IL-15, and IL-21, which play an important role in peripheral T cell expansion and survival, were found to up-regulate PD-1 and, with the exception of IL-21, PD-L1 on purified T cells in vitro. This effect was most prominent on memory T cells. Furthermore, these cytokines induced, indirectly, the expression of PD-L1 and PD-L2 on monocytes/macrophages in PBMC. The in vivo correlate of these observations was confirmed on PBMC isolated from HIV-infected individuals receiving IL-2 immunotherapy. Exposure of γc cytokine pretreated T cells to PD-1 ligand-IgG had no effect on STAT5 activation, T cell proliferation, or survival driven by γc cytokines. However, PD-1 ligand-IgG dramatically inhibited anti-CD3/CD28-driven proliferation and Lck activation. Furthermore, following restimulation with anti-CD3/CD28, cytokine secretion by both γc cytokine and anti-CD3/CD28 pretreated T cells was suppressed. These data suggest that γc cytokine-induced PD-1 does not interfere with cytokine-driven peripheral T cell expansion/survival, but may act to suppress certain effector functions of cytokine-stimulated cells upon TCR engagement, thereby minimizing immune-mediated damage to the host.
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