The tick saliva immunosuppressor, Salp15, contributes to Th17-induced pathology during Experimental Autoimmune Encephalomyelitis

Abstract

Summary Salp15 is a tick saliva protein that inhibits CD4+ T cell differentiation through its interaction with CD4. The protein inhibits early signaling events during T cell activation and IL-2 production. Because murine experimental autoimmune encephalomyelitis development is mediated by central nervous system-infiltrating CD4+ T cells that are specific for myelin-associated proteins, we sought to determine whether the treatment of mice with Salp15 during EAE induction would prevent the generation of proinflammatory T cell responses and the development of the disease. Surprisingly, Salp15-treated mice developed more severe EAE than control animals. The treatment of EAE-induced mice with the tick saliva protein did not result in increased infiltration of T cells to the central nervous system, indicating that Salp15 had not affected the permeability of the blood-brain barrier. Salp15 treatment did not affect the development of antibody responses against the eliciting peptide or the presence of IFNγ in the sera. The treatment with Salp15 resulted, however, in the increased differentiation of Th17 cells in vivo, as evidenced by higher IL-17 production from PLP139-151-specific CD4+ T cells isolated from the central nervous system and the periphery. In vitro, Salp15 was able to induce the differentiation of Th17 cells in the presence of IL-6 and the absence of TGFβ These results suggest that a conductive milieu for the differentiation of Th17 cells can be achieved by restriction of the production of IL-2 during T cell differentiation, a role that may be performed by TGFβ and other immunosuppressive agents.

Ixodes ricinus Salivary Serpin IRS-2 Affects Th17 Differentiation via Inhibition of the Interleukin-6/STAT-3 Signaling Pathway

“…Similar results, showing that tick saliva inhibits the Th17 subset, were reported by Skallova and colleagues, who showed that saliva-exposed DCs failed to induce efficient Th1 and Th17 polarization and promoted development of Th2 responses (42). Interestingly, treatment with Salp15, which also inhibits IL-6 production in dendritic cells, was shown to increase the differentiation of Th17 cells in vivo, as evidenced by higher IL-17 production from PLP139-151-specific CD4 ϩ T cells isolated from the central nervous system and the periphery (43).…”

Salp15, a Multifunctional Protein From Tick Saliva With Potential Pharmaceutical Effects

“…Furthermore, flow cytometry was used to detect the binding of Salp15 to CD4 for up to 72 h; the results suggested that the binding reaction between CD4 and salivary protein is persistent (65). However, deletion of the salivary protein C-terminal peptide P11 (Salp15 P11) results in a significant reduction in the capacity of Salp15 to bind to CD4+ T cells and a consequential lack of biological activity (65,66). Understanding the function and conformation of Salp15 can facilitate the development of highly specific pharmacological agents, such as monoclonal antibodies (mAbs) or Salp 15-like peptides, for special uses.…”

“…The Th17 can promote neutrophilic inflammation in the development of AHR; such inflammation is related to the severity of asthma (100,101). However, Juncadella et al (66) showed that the differentiation of Th17 cells is increased in the presence of Salp15, both in vivo and in vitro.…”

“…This may be due to the fact that Salp15 inhibits the production of IL-2, thus interfering with the balance between cytokines and increasing the differentiation of Th17 cells (66). This is probably the mechanism by which Salp15 exerts a therapeutic effect on allergic asthma.…”

“…A previous description considered Salp15 as a precursor of treatments for autoimmune diseases, whereas another investigation has shown the opposite effect in murine experimental autoimmune encephalomyelitis (EAE), which mimics multiple sclerosis (66). The occurrence and progression of EAE is associated with myelin-specific CD4+ T cell activation.…”