Innate immunity modulates autoimmunity: type 1 interferon‐β treatment in multiple sclerosis promotes growth and function of regulatory invariant natural killer T cells through dendritic cell maturation

Abstract

Summary Type 1 interferon‐β (T1IFN‐β) is an innate cytokine and the first‐choice therapy for multiple sclerosis (MS). It is still unclear how T1IFN‐β, whose main function is to promote innate immunity during infections, plays a beneficial role in autoimmune disease. Here we show that T1IFN‐β promoted the expansion and function of invariant natural killer (iNKT) cells, an innate T‐cell subset with strong immune regulatory properties that is able to prevent autoimmune disease in pre‐clinical models of MS and type 1 diabetes. Specifically, we observed that T1IFN‐β treatment significantly increased the percentages of Vα24+ NKT cells in peripheral blood mononuclear cells of MS patients. Furthermore, iNKT cells of T1IFN‐β‐treated individuals showed a dramatically improved secretion of cytokines (interleukins 4 and 5 and interferon‐γ) in response to antigenic stimulation compared to iNKT cells isolated from the same patients before T1IFN‐β treatment. The effect of T1IFN‐β on iNKT cells was mediated through the modulation of myeloid dendritic cells (DCs). In fact, DCs modulated in vivo or in vitro by T1IFN‐β were more efficient antigen‐presenting cells for iNKT cells. Such a modulatory effect of T1IFN‐β was associated with up‐regulation on DCs of key costimulatory molecules for iNKT (i.e. CD80, CD40 and CD1d). Our data identified the iNKT cell/DC pathway as a new target for the immune regulatory effect of T1IFNs in autoimmune diseases and provide a possible mechanism to explain the clinical efficacy of T1IFN‐β in MS.

Mesenchymal Stem Cells Overexpressing IFN-β Inhibit Breast Cancer Growth and Metastases through Stat3 Signaling in a Syngeneic Tumor Model

“…IFN-β functions as an immunomodulator in stimulating innate immunity to viral infections by activating natural killer cells and macrophages (49). Reports have also indicated that IFN-β can stimulate CD8+ T cells (50).…”

Invariant NKT Cells Regulate Experimental Autoimmune Encephalomyelitis and Infiltrate the Central Nervous System in a CD1d-Independent Manner

“…In this perspective of cytokine-mediated activation, it is interesting to find that IFN-␤, currently the most prescribed treatment for MS, drives the expansion of circulating NKT cells (64), an effect that might combine the IFN-␤-mediated maturation of DCs and its capacity to induce IL-15 essential for the homeostasis of NKT cells (13, 64 -66). Further understanding of the mechanisms driving NKT cell activation in the absence of exogenous ligands should provide novel targets for immune intervention in MS.…”

Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis

“…56,57 Importantly, the prevalence and function of iNKT cells was restored in patients in remission due to treatment with IFN-b. 58 Another study analysed untreated patients in remission, and found instead a further reduction in iNKT cells but evidence for a Th2-bias in the cytokine profile of iNKT cell lines established from these patients. 59 A Th2 bias in the cytokine profile of iNKT cells was also observed in patients treated with oral corticosteroids, suggesting that iNKT cells might exert immunoregulatory effects in MS by producing Th2 cytokines.…”