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

Interferon-beta (IFN-β) 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-β is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-β 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-β in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-β, and in vivo in whole blood samples of 32 untreated and 24 IFN-β treated MS patients, including 13 patients longitudinal. IFN-β 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-β 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-β (P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-β 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-β in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-β treatment at early timepoints during IFN-β therapy.