T-cell activation by recombinant receptors: CD28 costimulation is required for interleukin 2 secretion and receptor-mediated T-cell proliferation but does not affect receptor-mediated target cell lysis

Cancer Res. 2001 Mar 1;61(5):1976-82.

Abstract

Recombinant T-cell receptors with antibody-like specificity are successfully used to direct CTLs toward a MHC-independent immune response against target cells. Here we monitored the specific activation of receptor grafted CTLs in the context of CD28 costimulation. Peripheral blood T cells were retrovirally engrafted with recombinant anti-CD30 and anti-carcinoembryonic antigen receptors, respectively, that harbor either the Fc epsilonRI-gamma or the CD3-zeta intracellular signaling domain. Cross-linking of recombinant receptors by solid-phase bound ligand, i.e., CD30 and a carcinoembryonic antigen receptor-specific anti-idiotypic antibody, respectively, induces IFN-gamma secretion that is further enhanced by CD28 costimulation of grafted T cells. Induction of interleukin (IL)-2 secretion, in contrast, requires CD28 costimulation in addition to receptor cross-linking, irrespective of T-cell preactivation by anti-CD3 monoclonal antibody plus IL-2 or by anti-CD3 monoclonal antibody plus anti-CD28 monoclonal antibody. Accordingly, induction of IL-2 secretion upon receptor cross-linking by membrane-bound antigen requires CD28/B7 costimulation whereas IFN-gamma secretion and cell proliferation does not. The efficiency of cytolysis by receptor-grafted CTLs does not depend on and is not affected by CD28 costimulation. The data demonstrate that CTL proliferation, cytokine secretion, and cytolysis upon receptor cross-linking are differentially modulated by CD28 costimulation and that cytolysis does not require B7 expression on target cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology
  • B7-2 Antigen
  • CD28 Antigens / immunology*
  • CHO Cells
  • Carcinoembryonic Antigen / immunology
  • Carrier Proteins / immunology
  • Cell Division / immunology
  • Coculture Techniques
  • Cricetinae
  • Cytotoxicity, Immunologic / immunology
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism*
  • Ki-1 Antigen / immunology
  • Lymphocyte Activation / immunology*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Mutagenesis, Insertional
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / biosynthesis
  • Receptors, Antigen, T-Cell / blood
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Cell Surface*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transfection

Substances

  • Antigens, CD
  • B7-1 Antigen
  • B7-2 Antigen
  • CD28 Antigens
  • CD86 protein, human
  • Carcinoembryonic Antigen
  • Carrier Proteins
  • Interleukin-2
  • Ki-1 Antigen
  • Membrane Glycoproteins
  • Receptors, Antigen, T-Cell
  • Receptors, Cell Surface
  • Recombinant Proteins
  • carcinoembryonic antigen binding protein, human
  • Interferon-gamma