X-linked lymphoproliferative disease (XLP) is a human immunodeficiency syndrome caused by mutations in the gene encoding the adaptor molecule SAP (signalling lymphocytic activation molecule (SLAM)-associated protein). SAP-deficient humans and mice have normal numbers of T cells, B cells and natural killer (NK) cells, but their T cells and NK cells have functional defects that lead to impaired immune responses. Now, Kim Nichols and colleagues show that SAP deficiency blocks the development of natural killer T (NKT) cells and that this seems to be a contributory factor in XLP.

SAP is known to recruit the SRC-family kinase FYN to receptors of the SLAM family. As FYN is known to be required for the development of NKT cells, the authors speculated that NKT-cell defects might contribute to XLP. Reverse-transcriptase PCR analysis showed that SAP is expressed by NKT cells from wild-type mice. When splenocytes from SAP-deficient mice were treated with the NKT-cell-specific agonist α-galactosylceramide, they failed to produce detectable levels of interferon-γ and interleukin-4. To determine whether the NKT-cell defect is quantitative or qualitative, cells from SAP-deficient mice were analysed by flow cytometry: significantly fewer NKT cells were found in SAP-deficient mice than in wild-type mice, indicating that the defect is quantitative.

The authors next asked whether the defect is intrinsic to SAP-deficient haematopoietic cells or non-haematopoietic cells. In experiments using bone-marrow chimeras, NKT cells could develop only from wild-type bone-marrow cells, so the defect is haematopoietic-cell autonomous. When 17 patients with XLP were examined, the authors observed a 97% reduction in NKT-cell numbers in peripheral blood compared with individuals who do not have XLP. Genetic analysis of a female carrier of XLP revealed that X-chromosome inactivation was skewed in NKT cells but not in T or B cells, supporting the idea that SAP is required for NKT-cell development but is dispensable for T- and B-cell development.

This study shows that SAP is crucial for the development of NKT cells in humans and mice and that lack of NKT cells might contribute to XLP. It is not clear which SLAM-family member is associated with SAP in NKT cells, and the details of the signalling pathway have yet to be worked out.