Contact-Dependent Interference with Invariant NKT Cell Activation by Herpes Simplex Virus-Infected Cells

Abstract

Invariant CD1d-restricted natural killer T (iNKT) cells play important roles in generating protective immune responses against infections. Here, we have investigated the role of human iNKT cells in HSV-1 infection and their interaction with epidermal keratinocytes. These cells express CD1d and are the primary target of the virus. Keratinocytes loaded with α-GalCer could stimulate IFN-γ production and CD25 upregulation by iNKT cells. However, both α-GalCer- and cytokine-dependent activation of iNKT cells was impaired after coculture with HSV-1-infected cells. Interestingly, CD1d downregulation was not observed on infected keratinocytes, which were also found to inhibit TCR-independent iNKT cell activation. Further examination of the cytokine profile of iNKT/keratinocyte cocultures showed inhibition of IFN-γ, IL-5, IL-10, IL-13 and IL-17 secretion, but upregulation of IL-4 and TNF-α following the infection. Moreover, cell-to-cell contact between infected keratinocytes and iNKT cells was required for the inhibition of activation, as the cell-free supernatants containing virus did not affect activation. Productive infection of iNKT cells was however not required for the inhibitory effect. Following coculture with infected cells, iNKT cells were no longer responsive to further stimulation with α-GalCer-loaded CD1d. We found that exposure to HSV-1-infected cells resulted in impaired TCR signalling downstream of ZAP70. Additionally, infected cells upregulated the expression of the negative T cell regulator, galectin-9; however, blocking experiments indicated that the impairment of iNKT cell responses was independent of galectin-9. Thus, interference with activation of human iNKT cells by HSV-1 may represent a novel immunoevasive strategy utilized by the virus to avoid immune clearance.

A VP22-Null HSV-1 Is Impaired in Inhibiting CD1d-Mediated Antigen Presentation

“…2A). Consistent with previous reports (6,25,33,45), an HSV-1 infection reduced the ability of CD1d molecules to recycle back to the cell surface (Fig. 2B).…”

“…We and others have shown that HSV-1 can inhibit CD1d-mediated antigen presentation to NKT cells by suppressing CD1d recycling (6,25,33,45). This inhibition of NKT cell function by HSV-1 is dependent on cell-to-cell contact of infected APCs and NKT cells, but not due to infection of NKT cells (6).…”

A Thr/Ser dual residue motif in the cytoplasmic tail of human CD1d is important for the down‐regulation of antigen presentation following a herpes simplex virus 1 infection

“…Upon infection of CD1d + cells by many viruses, including varicella virus, vesicular stomatitis virus and HIV, CD1d molecules are reduced on the cell surface . Infections by HSV, like those by other viruses, also suppress CD1d‐mediated activation of NKT cells, probably by inhibiting the transport of newly synthesized CD1d molecules to the cell surface …”

NKT Cells Determine Titer and Subtype Profile of Virus-Specific IgG Antibodies during Herpes Simplex Virus Infection

“…HSV-1 is known to interfere with CD1d Ag presentation (10,11,28) and to impair TCR signaling in iNKT cells (9). In contrast, mice are more resistant to HSV-associated immune evasion mechanisms.…”

“…Experiments with human cells have shown that HSV-1 interferes with CD1d Ag presentation and NKT cell activation (9)(10)(11). Finally, there is direct evidence from murine HSV-1 and HSV-2 infection models that iNKT cells contribute to virus control (12,13).…”