Different interleukin‐17‐secreting Toll‐like receptor⁺ T‐cell subsets are associated with disease activity in multiple sclerosis

Abstract

Signalling through Toll-like receptors (TLRs) may play a role in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). In the present study, the expression of TLR-2, -4 and -9 was significantly higher on CD4 and CD8 T-cells from MS patients compared to healthy individuals. Following in-vitro activation, the proportion of interleukin (IL)-17 and IL-6 CD4 and CD8 T-cells was higher in the patients. In addition, the proportion of IFN-γ-secreting TLR CD8 T-cells was increased in MS patients. Among different IL-17 T-cell phenotypes, the proportion of IL-17 TLR CD4 and CD8 T-cells producing IFN-γ or IL-6 were positively associated with the number of active brain lesions and neurological disabilities. Interestingly, activation of purified CD4 and CD8 T-cells with ligands for TLR-2 (Pam3Csk4), TLR-4 [lipopolysaccharide (LPS)] and TLR-9 [oligodeoxynucleotide (ODN)] directly induced cytokine production in MS patients. Among the pathogen-associated molecular patterns (PAMPs), Pam3Csk4 was more potent than other TLR ligands in inducing the production of all proinflammatory cytokines. Furthermore, IL-6, IFN-γ, IL-17 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels produced by Pam3Csk4-activated CD4 cells were directly associated with disease activity. A similar correlation was observed with regard to IL-17 levels released by Pam3Csk4-stimulated CD8 T-cells and clinical parameters. In conclusion, our data suggest that the expansion of different T helper type 17 (Th17) phenotypes expressing TLR-2, -4 and -9 is associated with MS disease activity, and reveals a preferential ability of TLR-2 ligand in directly inducing the production of cytokines related to brains lesions and neurological disabilities.

Bystander CD4+ T cells: crossroads between innate and adaptive immunity

“…TLR2 is an important PRR for the recognition of bacterial lipoteichoic acid, lipoproteins, and peptidoglycans 53 . Previous studies have demonstrated the functional role of TLR2 in effector/memory CD4 + T cells [54][55][56][57][58][59][60][61][62] . TLR2 agonists can act directly on effector T H 1 cells to induce production of IFN-γ in the absence of TCR stimulation.…”

Pattern Recognition Receptors in Multiple Sclerosis and Its Animal Models

“…As discussed below, later EAE studies suggest that TLR2 can in fact be protective (14–16) through a mechanism known as TLR tolerance. Beyond TLR2, other receptors including TLR3 and TLR4 are also expressed in active MS lesions (8), and TLR2, TLR4, TLR9 all showed elevated expression on CD4 + and CD8 + T cells from MS patients (9, 17). Expression of TLRs by T H 17 cells in particular was shown to correlate with the extent of brain lesions and neurological disabilities in MS (17).…”

Selective serotonin reuptake inhibitor attenuates the hyperresponsiveness of TLR2+ and TLR4+ Th17/Tc17‐like cells in multiple sclerosis patients with major depression

“…. Other cytokines, such as IL‐21, IL‐22 and GM‐CSF, are also produced by some encephalitogenic CD4 + T cells 20‐25 . Finally, cytotoxic CD8 + T cells may not only cause oligodendrocyte death and neuronal damage through release of cytotoxic molecules, but also may potentiate brain lesions by secreting IFN‐γ (Tc‐1) or IL‐17 (Tc‐17) 26‐31 .…”

“…Indeed, elevated TLR expression was observed in peripheral blood monocular cells (PBMCs) of MDD patients 40 . Due to their immune adjuvant properties on DCs, signalling via TLRs by molecular patterns from both pathogens (PAMPs) has been implicated in the pathogenesis of autoimmune diseases, such as MS 20,41 . Ligands for TLR2 (lipopeptides) and TLR4 (lipopolysaccharides)cy from pathogens can have an adverse impact on MS by increasing the production of IL‐1β, IL‐6 and IL‐23 by DCs 42,43 .…”