The adaptor protein in question—SAP (SLAM-associated protein)—is expressed in T, NK, and NKT cells and responds to SLAM family receptors by recruiting and activating the downstream tyrosine kinase Fyn. Fyn was known to be required for NKT cell development in the thymus, but the upstream cell surface signals remained unknown.

Pasquier and colleagues now implicate the SLAM family of receptors in NKT cell development by showing that the loss of SAP results in a complete absence of NKT cells in both mice and humans. SAP-transmitted signaling events were uniquely required for the development of NKT cells, as conventional T cells and NK cells developed normally in the absence of SAP.

The need for SAP-mediated signals may reflect the unique requirements for positive selection of NKT cells in the thymus. Whereas conventional T cells interact with thymic epithelial cells for selection, NKT cells must interact with CD1d-expressing thymocytes via their invariant T cell receptors. This unique interaction might also provide the required SLAM-mediated signals.

In an intriguing twist, mutations in SAP cause a fatal disease called X-linked lymphoproliferative syndrome (XLP), which is characterized by uncontrolled Epstein-Barr virus (EBV) infections and B cell lymphomas. The loss of SAP impacts the function of multiple cell types including NK cells and T cells, but based on the current study, NKT cells may also contribute to XLP. Studying NKT cell activation during human EBV infection may give clues about why the lack of SAP, which results in so many immune cell defects, would preferentially increase susceptibility to only one type of virus.