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The role of natural killer T cells in X-linked lymphoproliferative disease Chung, Brian Kai-Ho


X-linked lymphoproliferative disease (XLP) is a fatal immunodeficiency syndrome characterized by fulminant infectious mononucleosis (IM), uncontrolled lymphoproliferation and B cell malignancies following infection with the Epstein-Barr virus (EBV). In the majority of affected individuals, XLP is caused by mutations to the gene Src homology 2-domain 1A (SH2D1A), which encodes for signaling lymphocyte activation molecule-associated protein (SAP). Studies in SAP-deficient (SAP-/-) mice and in humans with XLP indicate that SAP is necessary for the normal function of several immune cell populations including natural killer (NK) cells, CD4⁺ helper T (TH) cells and CD8⁺ cytotoxic T lymphocytes (CTL). Surprisingly despite these immune cell defects, individuals with XLP appear immuno-competent against most pathogens and only develop disease upon exposure to EBV. Why EBV infection specifically triggers XLP in humans with defective SAP expression is not fully understood, however, we observed that SAP-/- mice and XLP subjects completely lack the immune subset of natural killer T (NKT) cells. Given that NKT cells are known to play an important role in controlling immune responses and that XLP subjects generate dysregulated immune responses following EBV infection, we hypothesized that NKT cells may directly control the proliferation of EBV-infected B cells. To test this hypothesis, we established an in vitro experimental system using human NKT cell lines and EBV-transformed tonsillar B cells. EBV transformation of naïve B cells into lymphoblastoid cell lines (LCL) resulted in the downregulation of the NKT cell antigen-presenting molecule CD1d and correlated with the inability of LCL to activate NKT cells, even in the presence of the superagonist α-galactosylceramide (αGalCer). By contrast, LCL with induced CD1d expression strongly activate NKT cell effector functions even in the absence of αGalCer. Collectively, these results demonstrate that NKT cells may be critical for controlling early EBV replication in B cells prior to CD1d downregulation and suggest that the absence of NKT cells may underlie the immune dysregulation in XLP subjects following EBV infection.

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