Research ArticleImmunodeficiency

Inhibition of diacylglycerol kinase α restores restimulation-induced cell death and reduces immunopathology in XLP-1

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Science Translational Medicine  13 Jan 2016:
Vol. 8, Issue 321, pp. 321ra7
DOI: 10.1126/scitranslmed.aad1565

SAPping immunopathology

Individuals with deficient immune systems may also paradoxically experience hyperimmune side effects. X-linked lymphoproliferative disease (XLP-1)—an immunodeficiency caused by defects in the T cell receptor adaptor protein SAP [signaling lymphocytic activation molecule (SLAM)–associated protein]—is associated with expansion of activated T cell after viral infection. Now, Ruffo et al. report that down-regulating diacylglycerol kinase α (DGKα) in SAP-deficient T cells restores restimulation-induced cell death, preventing this excess expansion. If these data hold true in humans, targeting DGKα may prevent viral-induced immunopathology in XLP-1 patients.


X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8+ T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)–associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)–induced signaling. SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCθ (protein kinase Cθ). We show that down-regulation of DGKα activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGKα prevents the excessive CD8+ T cell expansion and interferon-γ production that occur in SAP-deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGKα as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients.

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