OX40 ligation of CD4+ T cells enhances virus-specific CD8+ T cell memory responses independently of IL-2 and CD4+ T regulatory cell inhibition

J Immunol. 2006 Feb 15;176(4):2486-95. doi: 10.4049/jimmunol.176.4.2486.

Abstract

We have previously shown that CD4(+) T cells are required to optimally expand viral-specific memory CD8(+) CTL responses using a human dendritic cell-T cell-based coculture system. OX40 (CD134), a 50-kDa transmembrane protein of the TNFR family, is expressed primarily on activated CD4(+) T cells. In murine models, the OX40/OX40L pathway has been shown to play a critical costimulatory role in dendritic cell/T cell interactions that may be important in promoting long-lived CD4(+) T cells, which subsequently can help CD8(+) T cell responses. The current study examined whether OX40 ligation on ex vivo CD4(+) T cells can enhance their ability to "help" virus-specific CTL responses in HIV-1-infected and -uninfected individuals. OX40 ligation of CD4(+) T cells by human OX40L-IgG1 enhanced the ex vivo expansion of HIV-1-specific and EBV-specific CTL from HIV-1-infected and -uninfected individuals, respectively. The mechanism whereby OX40 ligation enhanced help of CTL was independent of the induction of cytokines such as IL-2 or any inhibitory effect on CD4(+) T regulatory cells, but was associated with a direct effect on proliferation of CD4(+) T cells. Thus, OX40 ligation on CD4(+) T cells represents a potentially novel immunotherapeutic strategy that should be investigated to treat and prevent persistent virus infections, such as HIV-1 infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Epstein-Barr Virus Infections / immunology
  • Epstein-Barr Virus Infections / metabolism
  • Epstein-Barr Virus Infections / virology
  • Gene Expression Regulation
  • HIV Infections / immunology
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / immunology
  • Herpesvirus 4, Human / immunology
  • Humans
  • Immunologic Memory / immunology*
  • Interleukin-2 / immunology*
  • Membrane Glycoproteins / immunology
  • OX40 Ligand
  • Receptors, Interleukin-2 / metabolism
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Tumor Necrosis Factors / immunology

Substances

  • Interleukin-2
  • Membrane Glycoproteins
  • OX40 Ligand
  • Receptors, Interleukin-2
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor
  • TNFRSF4 protein, human
  • TNFSF4 protein, human
  • Tumor Necrosis Factors