Effects of interferon-beta on co-signaling molecules: upregulation of CD40, CD86 and PD-L2 on monocytes in relation to clinical response to interferon-beta treatment in patients with multiple sclerosis

Mult Scler. 2008 Mar;14(2):166-76. doi: 10.1177/1352458507081342. Epub 2007 Oct 17.


Interferon-beta (IFN-beta) reduces disease activity in a subgroup of patients with relapsing remitting multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-beta is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-beta on the expression of co-signaling pathways (CD28-CD80/CD86, CD154-CD40, ICOS-ICOSL, PD-1-PD-L1/2) in MS patients and correlated the results with the clinical response to IFN-beta in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-beta, and in vivo in whole blood samples of 32 untreated and 24 IFN-beta treated MS patients, including 13 patients longitudinal. IFN-beta treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on monocytes as well as PD-L1 on CD4+-T-cells in vitro and in vivo. IFN-beta treated MS patients were grouped into responders and non-responders on the basis of Kurtzkés EDSS (expanded disability status scale) progression and relapse rate. Upregulation of CD40, CD86 and PD-L2 on monocytes was associated with treatment response to IFN-beta (P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-beta upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-beta in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-beta treatment at early timepoints during IFN-beta therapy.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Adult
  • Antibodies / blood
  • Antigens, CD / metabolism*
  • B7-2 Antigen / metabolism*
  • B7-H1 Antigen
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Antigens / metabolism*
  • Female
  • Flow Cytometry
  • Humans
  • Immunologic Factors / administration & dosage*
  • Immunologic Factors / immunology
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interferon-beta / administration & dosage*
  • Interferon-beta / immunology
  • Male
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / immunology
  • Monocytes / metabolism
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy*
  • Multiple Sclerosis, Relapsing-Remitting / immunology
  • Multiple Sclerosis, Relapsing-Remitting / metabolism
  • Programmed Cell Death 1 Ligand 2 Protein
  • STAT1 Transcription Factor / drug effects
  • STAT1 Transcription Factor / immunology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology


  • Antibodies
  • Antigens, CD
  • B7-2 Antigen
  • B7-H1 Antigen
  • CD274 protein, human
  • CD40 Antigens
  • CD86 protein, human
  • Immunologic Factors
  • Intercellular Signaling Peptides and Proteins
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • STAT1 Transcription Factor
  • Interferon-beta