Costimulation through OX40 is crucial for induction of an alloreactive human T-cell response

Immunology. 2003 Jun;109(2):226-31. doi: 10.1046/j.1365-2567.2003.01648.x.


The alloreactive immune response is a series of events initiated by the interaction of T cells with allogeneic dendritic cells (DCs), involving alloantigen recognition and costimulatory signals. In this study, we investigated the role of OX40 in alloreactivity in vitro. We first demonstrated that anti-OX40 ligand (anti-OX40L) monoclonal antibody (mAb) could markedly suppress the mixed leucocyte reaction (MLR) of peripheral blood mononuclear cells (PBMC). To further define the contribution of the OX40/OX40L system to the MLR, we set up a co-culture system of CD4+ T cells and allogeneic monocyte-derived dendritic cells (DCs). After 2 days, OX40 expression was induced on CD4+ T cells and this induction was strongly inhibited by the addition of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-Fc fusion protein, suggesting that the expression of OX40 during alloreaction is dependent on CD28 signalling. Next we examined the effects of anti-OX40L mAb, CTLA-4-Fc fusion protein and anti-human leucocyte antigen (HLA)-DR mAb on the proliferative response of CD4+ T cells to allogeneic DCs. The proliferation of T cells was almost completely suppressed by anti-OX40L mAb, which was comparable with that of CTLA-4-Fc. Measurement of interleukin-2 (IL-2) production in the culture supernatants showed that suppression of a proliferative response was at least in part ascribed to reduced IL-2 production. Furthermore, purified OX40L- allogeneic DCs could induce considerable proliferation of CD4+ T cells, which was suppressed by anti-OX40L mAb. These results suggest that the OX40/OX40L system is crucial for induction of the allogeneic T-cell response and the OX40/OX40L system is subsequent to and dependent on CD28 signalling, but is crucial for the end outcome of the human alloreactive T-cell response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Antibodies, Monoclonal / immunology
  • Antigens, CD
  • Antigens, Differentiation / immunology
  • CD28 Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen
  • Cell Division / immunology
  • Coculture Techniques
  • Dendritic Cells / immunology
  • Humans
  • Immune Tolerance
  • Immunoconjugates*
  • Interleukin-2 / metabolism
  • Isoantigens / immunology*
  • Lymphocyte Culture Test, Mixed
  • Membrane Glycoproteins / immunology
  • Monocytes / immunology
  • OX40 Ligand
  • Receptors, Immunologic / immunology
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor*
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism


  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation
  • CD28 Antigens
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Immunoconjugates
  • Interleukin-2
  • Isoantigens
  • Membrane Glycoproteins
  • OX40 Ligand
  • Receptors, Immunologic
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • TNFRSF4 protein, human
  • TNFSF4 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Abatacept