Abstract
Abstract Mutations in the SH2D1A gene, that encodes SLAM-associated protein (SAP), cause X-linked lymphoproliferative disease (XLP), a rare congenital immunodeficiency defined by exquisite sensitivity to Epstein-Barr virus (EBV). The inability of boys with XLP to control EBV infection results in fulminant, often fatal, infectious mononucleosis, massive expansions of EBV-infected B cells and malignant B cell lymphomas. However, the precise mechanism of how SAP loss contributes to susceptibility to EBV remains unclear. Given the unique B cell tropism of EBV and the purported role of SAP in regulating lymphocyte/lymphocyte interactions, we hypothesized that SAP expression within CD8 T cells is critical for T cells to mount responses towards antigen-expressing B cells. Wild type and Sh2d1a-/- CD8 T cells responded strongly when stimulated in vitro with cognate antigen-coated whole splenocytes. However, Sh2d1a-/- CD8 T cells exhibited greatly diminished proliferation and effector functions relative to wild type CD8 T cells when cultured with antigen-coated B cells in vitro or challenged with antigen-expressing B cell lymphoma in vivo. These results demonstrate that SAP is required for the priming of CD8 T cells when B cells act as the primary APC. Together, our findings suggest that the susceptibility of XLP patients to EBV infection may at least in part be a consequence of an inability of their naïve CD8 T cells to differentiate into effectors upon encountering virally-infected B cells.
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