Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses

J Immunol. 2003 Jan 15;170(2):711-8. doi: 10.4049/jimmunol.170.2.711.

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

  • Antibodies / physiology
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis*
  • Antigens, Differentiation, T-Lymphocyte / physiology
  • Antigens, Surface / biosynthesis
  • Antigens, Surface / immunology
  • Antigens, Surface / physiology*
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen*
  • B7-H1 Antigen
  • Blood Proteins / biosynthesis
  • Blood Proteins / physiology
  • CD28 Antigens / biosynthesis*
  • Cell Division / immunology
  • Cells, Cultured
  • Cytokines / physiology*
  • Down-Regulation / immunology
  • Humans
  • Inducible T-Cell Co-Stimulator Protein
  • Intercellular Signaling Peptides and Proteins
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-15 / biosynthesis*
  • Interleukin-2 / physiology
  • Interleukin-4 / biosynthesis*
  • Interleukin-7 / biosynthesis*
  • Interleukin-7 / physiology
  • Interleukins / biosynthesis*
  • Lymphocyte Activation / immunology*
  • Membrane Glycoproteins
  • Peptides / physiology
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Antigen, T-Cell / physiology*
  • Receptors, Interleukin-7 / physiology
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Antibodies
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • B7-1 Antigen
  • B7-H1 Antigen
  • Blood Proteins
  • CD274 protein, human
  • CD28 Antigens
  • Cytokines
  • ICOS protein, human
  • IL2RG protein, human
  • Inducible T-Cell Co-Stimulator Protein
  • Intercellular Signaling Peptides and Proteins
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-15
  • Interleukin-2
  • Interleukin-7
  • Interleukins
  • Membrane Glycoproteins
  • PDCD1 protein, human
  • PDCD1LG2 protein, human
  • Peptides
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-7
  • Interleukin-4
  • interleukin-21