Role of SAP-mediated inhibition of DGKa in regulating restimulation induced cell death (RICD): does DGKa targeting rescue RICD in XLP patients?

The X-linked lymphoproliferative syndrome (XLP-1) is an inherited primary immunodeficiency caused by loss of the function of the SAP protein, encoded by the SH21DA gene, and characterized by massive accumulation of activated immune cells, called lympho-histiocytosis. The latter is due to an abnormal immune reaction following Epstein-Barr virus (EBV)infection. Following the first wave of expansion, the majority of EBV- activated T lymphocytes lacking SAP fail to undergo cell death induced by continuous stimulation by the pathogen (RCID) , thus accumulating in liver and other tissues. SAP is a protein adaptor, involved in the regulation of the response of T lymphocytes to the activation of TCR, a T-cell specific membrane molecule (receptor) that after pathogen (the so called ‘antigen’) identification allows the activation of T- lymphocytes. Recent evidence showed that SAP mediates the inhibition of Diacylglycerol kinase alpha (DGKa), a protein acting downstream of the signaling cascade activated by the TCR. When SAP is not working properly, DGKa is constitutively active, thus hampering TCR signal transduction. Indeed, pharmacological inhibition of DGKa counteracts defects caused by SAP mutations: TCR signaling is restored as well as the induction of IL-2 (a molecule that regulates lymphocytes activity) . These evidences pave the way to investigate whether inhibition of DGKa may restore molecular features that are deregulated in SAP-deificient T cells, such as RICD, thus reducing tissue damage in XLP-1 patients and suggesting that DGKa is a valid target for new drug therapies.