Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP

We have introduced a targeted mutation in SH2D1A/DSHP/SAP, the gene respons ible for the human genetic disorder X-linked lymphoproliferative disease (X LP). SLAM-associated protein (SAP)-deficient mice had normal lymphocyte dev elopment, but on challenge with infectious agents, recapitulated features o f XLP. Infection of SAP(-) mice with lymphocyte choriomeningitis virus (LCM V) or Toxoplasma gondii was associated with increased T cell activation and IFN-gamma production, as well as a reduction of Ig-secreting cells. Anti-C D3-stimulated splenocytes from uninfected SAP(-) mice produced increased IF N-gamma and decreased IL-4, findings supported by decreased serum IgE level s in vivo. The Th1 skewing of these animals suggests that cytokine misregul ation may contribute to phenotypes associated with mutation of SH2D1A/SAP.