Tick saliva-induced programmed death-1 and PD-ligand 1 and its related host immunosuppression

Yamato Sajiki,Naoya Maekawa,Kei Watari,Benvindo Capela João,Itabajara Da Silva Vaz,Tomohiro Okagawa,Satoru Konnai,Kazuhiko Ohashi,Luís Fernando Parizi,Sotaro Fujisawa,Atsushi Kobayashi,Shiro Murata,Carlos Logullo,Yoshinori Ikenaka,Kevin Christian Montecillo Gulay

doi:10.1038/s41598-020-80251-y

Yamato Sajiki, Naoya Maekawa + Show 13 more

Open Access

https://doi.org/10.1038/s41598-020-80251-y

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Abstract

The tick Rhipicephalus microplus is a harmful parasite of cattle that causes considerable economic losses to the cattle breeding industry. Although R. microplus saliva (Rm-saliva) contains several immunosuppressants, any association between Rm-saliva and the expression of immunoinhibitory molecules, such as programmed death (PD)-1 and PD-ligand 1 (PD-L1), has not been described. In this study, flow cytometric analyses revealed that Rm-saliva upregulated PD-1 expression in T cells and PD-L1 expression in CD14+ and CD11c+ cells in cattle. Additionally, Rm-saliva decreased CD69 expression in T cells and Th1 cytokine production from peripheral blood mononuclear cells. Furthermore, PD-L1 blockade increased IFN-γ production in the presence of Rm-saliva, suggesting that Rm-saliva suppresses Th1 responses via the PD-1/PD-L1 pathway. To reveal the upregulation mechanism of PD-1/PD-L1 by Rm-saliva, we analyzed the function of prostaglandin E2 (PGE2), which is known as an inducer of PD-L1 expression, in Rm-saliva. We found that Rm-saliva contained a high concentration of PGE2, and PGE2 treatment induced PD-L1 expression in CD14+ cells in vitro. Immunohistochemical analyses revealed that PGE2 and PD-L1 expression was upregulated in tick-attached skin in cattle. These data suggest that PGE2 in Rm-saliva has the potential to induce the expression of immunoinhibitory molecules in host immune cells.

Highlights

The tick Rhipicephalus microplus is a harmful parasite of cattle that causes considerable economic losses to the cattle breeding industry
Prostaglandin E2 (PGE2) is an inflammatory mediator derived from arachidonic acid by several enzymes such as cyclooxygenase (COX)-1 and COX-219. PGE2 regulates the activity of immune cells, such as T cells, dendritic cells (DCs), and macrophages, contributing to immune evasion during cancer and chronic infection20. PGE2 inhibits Th1 immune responses, including T-cell proliferation and Th1 cytokine production in cattle[21]
We examined P GE2 concentrations in Rm-saliva by enzyme-linked immunosorbent assay (ELISA) and ultra-performance liquid chromatography (UPLC)–mass spectrometry (MS)/MS system, and we examined the association of PGE2 in Rm-saliva with programmed death (PD)-L1 expression by in vitro culture and immunohistochemistry

Summary

Introduction

The tick Rhipicephalus microplus is a harmful parasite of cattle that causes considerable economic losses to the cattle breeding industry. Immunohistochemical analyses revealed that PGE2 and PD-L1 expression was upregulated in tickattached skin in cattle. These data suggest that PGE2 in Rm-saliva has the potential to induce the expression of immunoinhibitory molecules in host immune cells. The Rhipicephalus microplus is a one-host tick that feeds on cattle It is one of the most harmful parasites of cattle in subtropical areas of the world and causes significant economic losses to the cattle industry[1]. PGE2 inhibits Th1 immune responses, including T-cell proliferation and Th1 cytokine production in cattle[21]. Numerous studies have revealed that tick saliva inhibits T-cell activation, especially Th1 cytokine p roduction[35,36]. We examined P GE2 concentrations in Rm-saliva by enzyme-linked immunosorbent assay (ELISA) and ultra-performance liquid chromatography (UPLC)–mass spectrometry (MS)/MS system, and we examined the association of PGE2 in Rm-saliva with PD-L1 expression by in vitro culture and immunohistochemistry

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