The immunosuppressive effect of the tick protein, Salp15, is long-lasting and persists in a murine model of hematopoietic transplant

Abstract

Salp15, a salivary protein of Ixodes ticks, inhibits the activation of naïve CD4 T cells. Treatment with Salp15 results in the inhibition of early signaling events and the production of the autocrine growth factor, interleukin-2. The fate of the CD4 T cells activated in the presence of Salp15 or its long-term effects are, however, unknown. We now show that Salp15 binding to CD4 is persistent and induces a long-lasting immunomodulatory effect. The activity of Salp15 results in sustained diminished cross-antigenic antibody production even after interruption of the treatment with the protein. Transcriptionally, the salivary protein provokes an acute effect that includes known activation markers, such as Il2 or Cd44, and that fades over time. The long-term effects exerted by Salp15 do not involve the induction of either anergy traits nor increased populations of regulatory T cells. Similarly, the treatment with Salp15 does not result in B cell anergy or the generation of myeloid suppressor cells. However, Salp15 induces the increased expression of the ectoenzyme, CD73, in regulatory T cells and increased production of adenosine. Our study provides a profound characterization of the immunomodulatory activity of Salp15 and suggests that its long-term effects are due to the specific regulation of CD73.

Wonders of tick saliva

“…In the epidermis, these are human CD8 + cytotoxic T cells or murine dendritic epidermal T cells (DETCs), and in the dermis, CD4 + T helper cells and dermal  T cells (Heath and Carbone, 2013). Salp15 inhibits activation of naïve CD4 + T A C C E P T E D M A N U S C R I P T cells through binding to the first domain of the CD4 co-receptor, impeding cell activation and inducing a long-lasting increasing immunomodulatory effect; in addition, Salp15 affects regulatory T cells (Tregs), inducing increased production of adenosine, a recognised immunosuppressive product (Garg et al, 2006;Tomás-Cortázar et al, 2017).…”

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

“…Other research has shown that Salp15 can bind to CD4 for extended periods of time and exert immunosuppressive effects. Purified splenic CD4+T cells, after being stimulated in the presence of Salp15 for 2 days, were then extensively washed and re-stimulated for another 2 days; the inhibitory effects of Salp15 on T cells were still observed, even after removing contact with salivary proteins after 4 days of activation (65). 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).…”

“…Purified splenic CD4+T cells, after being stimulated in the presence of Salp15 for 2 days, were then extensively washed and re-stimulated for another 2 days; the inhibitory effects of Salp15 on T cells were still observed, even after removing contact with salivary proteins after 4 days of activation (65). 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).…”

“…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.…”

Tick saliva and its role in pathogen transmission

“…The Salp15 binds to the CD4 coreceptor of mammalian T cells, inhibiting subsequent receptor ligand-induced early cell signalling, which explains its immunosuppressive activity and specificity for CD4 T cells [92]; however, Salp15 also binds to the C-type lectin receptor, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN, also known as CD209), inhibiting Toll-like receptor (TLR)-induced production of proinflammatory cytokines (including cytokines induced by B. burgdorferi) and dendritic cell-induced T cell activation [93]. The activity of Salp15 appears long lasting, possibly due to Salp15induced upregulation of CD73 (5 -ectonucleotidase) in regulatory T cells, which increases production of adenosine, a recognized immunosuppressant [94].…”