Abstract
The program death 1 (PD-1) receptor and its ligands, PD-1 ligand (PD-L)1 and PD-L2, define a novel regulatory pathway with potential inhibitory effects on T, B, and monocyte responses. In the present study, we show that human CD4(+) T cells express PD-1, PD-L1, and PD-L2 upon activation, and Abs to the receptor can be agonists or antagonists of the pathway. Under optimal conditions of stimulation, ICOS but not CD28 costimulation can be prevented by PD-1 engagement. IL-2 levels induced by costimulation are critical in determining the outcome of the PD-1 engagement. Thus, low to marginal IL-2 levels produced upon ICOS costimulation account for the greater sensitivity of this pathway to PD-1-mediated inhibition. Interestingly, exogenous IL-2, IL-7, and IL-15 but not IL-4 and IL-21 can rescue PD-1 inhibition, suggesting that among these cytokines only those that activate STAT5 can rescue PD-1 inhibition. As STAT5 has been implicated in the maintenance of IL-2Ralpha expression, these results suggest that IL-7 and IL-15 restore proliferation under conditions of PD-1 engagement by enhancing high-affinity IL-2R expression and hence, IL-2 responsiveness.
MeSH terms
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Antibodies / physiology
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte / biosynthesis*
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Antigens, Differentiation, T-Lymphocyte / physiology
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Antigens, Surface / biosynthesis
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Antigens, Surface / immunology
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Antigens, Surface / physiology*
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Apoptosis Regulatory Proteins
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B7-1 Antigen*
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B7-H1 Antigen
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Blood Proteins / biosynthesis
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Blood Proteins / physiology
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CD28 Antigens / biosynthesis*
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Cell Division / immunology
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Cells, Cultured
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Cytokines / physiology*
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Down-Regulation / immunology
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Humans
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Inducible T-Cell Co-Stimulator Protein
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Intercellular Signaling Peptides and Proteins
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Interleukin Receptor Common gamma Subunit
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Interleukin-15 / biosynthesis*
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Interleukin-2 / physiology
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Interleukin-4 / biosynthesis*
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Interleukin-7 / biosynthesis*
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Interleukin-7 / physiology
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Interleukins / biosynthesis*
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Lymphocyte Activation / immunology*
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Membrane Glycoproteins
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Peptides / physiology
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Receptors, Antigen, T-Cell / metabolism
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Receptors, Antigen, T-Cell / physiology*
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Receptors, Interleukin-7 / physiology
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Signal Transduction / immunology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
Substances
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Antibodies
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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Antigens, Surface
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-H1 Antigen
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Blood Proteins
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CD274 protein, human
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CD28 Antigens
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Cytokines
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ICOS protein, human
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IL2RG protein, human
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Inducible T-Cell Co-Stimulator Protein
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Intercellular Signaling Peptides and Proteins
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Interleukin Receptor Common gamma Subunit
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Interleukin-15
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Interleukin-2
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Interleukin-7
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Interleukins
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Membrane Glycoproteins
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PDCD1 protein, human
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PDCD1LG2 protein, human
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Peptides
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Receptors, Antigen, T-Cell
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Receptors, Interleukin-7
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Interleukin-4
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interleukin-21