Innate immune control of EBV-infected B cells by invariant natural killer T cells

Abstract

Key Points• B cells rapidly downregulate CD1d expression after EBV infection, thus abrogating iNKT cell recognition.• EBV-infected B cells induced to express CD1d elicit iNKT cell functions even in the absence of exogenous antigen.Individuals with X-linked lymphoproliferative disease lack invariant natural killer T (iNKT) cells and are exquisitely susceptible to Epstein-Barr virus (EBV) infection. To determine whether iNKT cells recognize or regulate EBV, resting B cells were infected with EBV in the presence or absence of iNKT cells. The depletion of iNKT cells increased both viral titers and the frequency of EBV-infected B cells. However, EBV-infected B cells rapidly lost expression of the iNKT cell receptor ligand CD1d, abrogating iNKT cell recognition. To determine whether induced CD1d expression could restore iNKT recognition in EBVinfected cells, lymphoblastoid cell lines (LCL) were treated with AM580, a synthetic retinoic acid receptor-a agonist that upregulates CD1d expression via the nuclear protein, lymphoid enhancer-binding factor 1 (LEF-1). AM580 significantly reduced LEF-1 association at the CD1d promoter region, induced CD1d expression on LCL, and restored iNKT recognition of LCL. CD1d-expressing LCL elicited interferon g secretion and cytotoxicity by iNKT cells even in the absence of exogenous antigen, suggesting an endogenous iNKT antigen is expressed during EBV infection. These data indicate that iNKT cells may be important for early, innate control of B cell infection by EBV and that downregulation of CD1d may allow EBV to circumvent iNKT cell-mediated immune recognition. (Blood. 2013;122(15):2600-2608

Expansion of highly activated invariant natural killer T cells with altered phenotype in acute dengue infection

“…iNKT cells are, like lymphocytes, innate, able to activate and produce large quantities of cytokines rapidly and have also been shown to have cytotoxic properties [10]. They are known to play an important role in both acute [11] and chronic viral infections [14,28], including a recent report on their role in dengue infection [12]. Acute dengue is known to associate with a marked lymphopenia [29], especially with reduction of T cells due to massive T cell apoptosis [8,9].…”

TLR9‐induced miR‐155 and Ets‐1 decrease expression of CD1d on B cells in SLE

“…Here, we demonstrated that TLR9-induced miR-155 could be one reason for the downregulation of CD1d. TLRs recognize different types of components from microbes, and EBV can reduce the expression of CD1d in B cells [12]. Thus, the dsDNA of EBV may induce the upregulation of miR-155 and the corresponding downregulation of CD1d in B cells.…”

“…A viral infection could downregulate the expression of CD1d [11,12]. However, the effect of cytosine guanine dinucleotide (CpG) on the expression of CD1d in B cells is unclear.…”

“…However, both decreased miR-155 and increased CD1d expression were observed after treatment with the JNK inhibitor, which indicated that the relative expression of miR-155 and CD1d could be regulated by the JNK pathway in B cells. Furthermore, previous studies have suggested that SLE is associated with EBV infection [12], and CD1d expression is decreased after EBV infection [15]. To explore whether the downregulation of CD1d is attributed to the high level of miR-155, we used human B-cell lines to examine this potential correlation.…”

“…Importantly, endogenous DNA stimulates inflammatory responses through TLR9 and exacerbates lupus disease pathology [9,10]. Viral infection could downregulate the expression of CD1d in APCs, such as B cells [11,12], DCs, and macrophages [13]. A number of exogenous viruses, especially Epstein-Barr virus (EBV) [14,15], also have been linked to the pathogenesis of SLE [16].…”