The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands.
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 gamma-chain (gamma c) 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 gamma c cytokine pretreated T cells to PD-1 ligand-IgG had no effect on STAT5 activation, T cell proliferation, or survival driven by gamma c 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 gamma c cytokine and anti-CD3/CD28 pretreated T cells was suppressed. These data suggest that gamma c 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.
Kinter
Audrey L
AL
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. AKinter@niaid.nih.gov
Godbout
Emily J
EJ
McNally
Jonathan P
JP
Sereti
Irini
I
Roby
Gregg A
GA
O'Shea
Marie A
MA
Fauci
Anthony S
AS
D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000276:immunology; D060890:B7-H1 Antigen; D002478:Cells, Cultured; D016207:Cytokines; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology* / Q000627:therapeutic use; D015851:Interleukin-7 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000276:immunology; D000098546:Interleukin-21
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D007378:Interleukins; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D000098546:Interleukin-21