4-1BB ligand induces cell division, sustains survival, and enhances effector function of CD4 and CD8 T cells with similar efficacy

J Immunol. 2001 Aug 1;167(3):1313-24. doi: 10.4049/jimmunol.167.3.1313.

Abstract

A costimulatory member of the TNFR family, 4-1BB, is expressed on activated T cells. Although some reports have suggested that 4-1BB is primarily involved in CD8 T cell activation, in this report we demonstrate that both CD4 and CD8 T cells respond to 4-1BB ligand (4-1BBL) with similar efficacy. CD4 and CD8 TCR transgenic T cells up-regulate 4-1BB, OX40, and CD27 and respond to 4-1BBL-mediated costimulation during a primary response to peptide Ag. 4-1BBL enhanced proliferation, cytokine production, and CTL effector function of TCR transgenic T cells. To compare CD4 vs CD8 responses to 4-1BBL under similar conditions of antigenic stimulation, we performed MLRs with purified CD4 or CD8 responders from CD28(+/+) and CD28(-/-) mice. We found that CD8 T cells produced IL-2 and IFN-gamma in a 4-1BBL-dependent manner, whereas under the same conditions the CD4 T cells produced IL-2 and IL-4. 4-1BBL promoted survival of CD4 and CD8 T cells, particularly at late stages of the MLR. CD4 and CD8 T cells both responded to anti-CD3 plus s4-1BBL with a similar cytokine profile as observed in the MLR. CD4 and CD8 T cells exhibited enhanced proliferation and earlier cell division when stimulated with anti-CD3 plus anti-CD28 compared with anti-CD3 plus 4-1BBL, and both subsets responded comparably to anti-CD3 plus 4-1BBL. These data support the idea that CD28 plays a primary role in initial T cell expansion, whereas 4-1BB/4-1BBL sustains both CD4 and CD8 T cell responses, as well as enhances cell division and T cell effector function.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand
  • Adjuvants, Immunologic / physiology
  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Viral / genetics
  • Antigens, Viral / immunology
  • CD28 Antigens / immunology
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Division / immunology
  • Cell Survival / immunology
  • Cells, Cultured
  • Drug Synergism
  • Epitopes, T-Lymphocyte / immunology
  • Glycoproteins / genetics
  • Glycoproteins / immunology
  • Interphase / immunology
  • Ligands
  • Lymphocyte Activation / genetics
  • Lymphocyte Culture Test, Mixed
  • Lymphocytic choriomeningitis virus / genetics
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Ovalbumin / genetics
  • Ovalbumin / immunology
  • Peptide Fragments / genetics
  • Peptide Fragments / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / biosynthesis
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / physiology*
  • Viral Proteins / genetics
  • Viral Proteins / immunology

Substances

  • 4-1BB Ligand
  • Adjuvants, Immunologic
  • Antibodies, Monoclonal
  • Antigens, Viral
  • CD28 Antigens
  • CD3 Complex
  • Epitopes, T-Lymphocyte
  • Glycoproteins
  • Ligands
  • OVA 323-339
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf4 protein, mouse
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Tumor Necrosis Factor-alpha
  • Viral Proteins
  • glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus
  • Ovalbumin