Varicella Zoster Virus Downregulates Expression of the Nonclassical Antigen Presentation Molecule CD1d

Abstract

Background The non-classical antigen presentation molecule CD1d presents lipid antigens to invariant natural killer T (iNKT) cells. Activation of these cells triggers a rapid cytokine response providing an interface between innate and adaptive immune responses. The importance of CD1d and iNKT cells in varicella zoster virus (VZV) infection has been emphasised by clinical reports of individuals with CD1d or iNKT cell deficiencies experiencing severe, disseminated varicella post-vaccination. Methods Three strains of VZV, VZV-S, rOka, and VZV rOka-66S were used to infect Jurkat cells. Flow cytometry of VZV- and mock-infected cells assessed the modulatory impact of VZV on CD1d. Infected cell-supernatant and transwell coculture experiments explored the role of soluble factors in VZV-mediated immunomodulation. CD1d transcripts were assessed by RT-qPCR. Results Surface and intracellular flow cytometry demonstrated CD1d was strikingly downregulated by VZV-S and rOka in both infected and VZV antigen-negative cells compared to mock. CD1d downregulation is cell-contact-dependant and CD1d transcripts are targeted by VZV. Mechanistic investigations using rOka-66S (unable to express the viral kinase ORF66), implicate this protein in CD1d modulation in infected cells. Conclusions VZV implements multiple mechanisms targeting both CD1d transcript and protein. This provides evidence of VZV interaction with and manipulation of the CD1d-iNKT cell axis.

Transcriptional and functional remodeling of lung-resident T cells and macrophages by Simian varicella virus infection

“…Prior studies revealed that subjects deficient in NK cells or CD1d molecule experience life-threatening varicella following infection or vaccination ( 33 – 35 ). Thus, we leveraged our scRNAseq dataset to understand the SVV-induced transcriptional changes in NK cell subsets.…”

Glycolipid antigen recognition by invariant natural killer T cells and its role in homeostasis and antimicrobial responses

“…iNKT cells play an important role in microbial infections. Their importance is evidenced by the fact that in some infections, pathogens adopt strategies to reduce CD1d expression ( 61 , 62 ). Although iNKT cells constitute a small population of T cells with a poor diversity of TCR, they enhance as well as regulate immune responses through the recognition of various glycolipid ligands ( Table 1 ).…”