Rat Cytomegalovirus-encoded γ-chemokine vXCL1 is a highly adapted, species-specific agonist for rat XCR1+ dendritic cells

Abstract

Dendritic cells (DC) expressing the chemokine receptor XCR1 are specialized in antigen cross-presentation to control infections with intracellular pathogens. XCR1+ DC are attracted by XCL1, a γ-chemokine secreted by activated CD8+ T cells and Natural Killer cells. Rat cytomegalovirus (RCMV) is the only virus known to encode a viral XCL1 analogue (vXCL1) that competes for XCR1 binding with the endogenous chemokine. Here we show that vXCL1 from two different RCMV strains as well as endogenous rat XCL1 (rXCL1) bind to and induce chemotaxis exclusively in rat XCR1+ DC. While rXCL1 activates the XCR1 Gi signaling pathway of rats and humans, both vXCL1 function as species-specific agonists for rat XCR1. In addition, we demonstrate constitutive internalization of XCR1 in XCR1-transfected HEK293A cells and in splenic XCR1+ DC. This internalization was independent of β-arrestin 1/2 and was enhanced after binding of vXCL1 and rXCL1, however, vXCL1 appeared as a stronger agonist. These findings suggest a decreased surface expression during DC cultivation at 37°C and subsequent impairment of chemotactic activity and XCR1+ DC function.