The signaling lymphocyte activation protein (SLAM) is an immunomodulatory receptor involved in regulating lymphocyte interactions and adhesion. The SLAM-associated protein (SAP) is required for SLAM signal mediation. SAP has been linked to the development of innate-like T cell lineages. SAP has also been shown to have an important role in the interactions between B cells and T cells that are instrumental in germinal center formation and long term humoral immunity. T cells lacking SAP do not maintain long-lasting interactions with B cells carrying antigens that would normally be recognized by the T cells. This observation likely explains the basis for many features of the disease known as XLP since individuals that are affected by XLP lack the SAP protein, fail to kill EBV-infected B cells and do not have germinal centers. The SAP-deficient mouse model recapitulates several features of XLP: hyperproliferative T cell response following infections, impaired NK and CD8 cell cytotoxicity, defective humoral immune responses, abnormal germinal center formation, reduction in IgG+ memory B cell numbers, and the absence of NKT and other innate T cells. It has been extensively used for studying germinal center responses and for analyses of innate T cell development. SAP protein is not present in these mice. The Sh2d1a gene is located on the X chromosome, so female knockouts are homozygous and male knockouts are hemizygous.
Genetic Background: C57BL/6 Background
The SAP Knockout mouse was generated in 2001 by Michael J. Czar and Pamela Schwartzberg of the National Human Genome Research Institute, NIH. The targeting construct was derived from a 129S6 Lambda phage library (Stratagene) and disrupts SAP in the second exon. Homologous recombinants were screened and chimeric mice were bred to C57BL6/J mice. The line was backcrossed to C57BL/6J for 10 generations. Taconic received stock in 2011.
Czar MJ, Kersh EN, Mijares LA, Lanier G, Lewis J, Yap G, Chen A, Sher A, Duckett CS, Ahmed R, Schwartzberg PL. (2001) Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. Proc Natl Acad Sci USA. 98(13):7449-54.
Crotty S, Kersh EN, Cannons J, Schwartzberg PL, Ahmed R. (2003) SAP is required for generating long-term humoral immunity. Nature 421(6920):282-7.
Cannons JL, Yu LJ, Jankovic D, Crotty S, HOrai R, Kirby M, Anderson S, Cheever AW, Sher A, Schwartzberg, PL. (2006) SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation. J Exp Med 203:1551-1565.
Qi H, Cannons JL, Klauschen F, Schwartzberg PL and Germain RN. (2008)SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455: 764-70.
Zhao, F, Cannons JL, Dutta M, Griffiths GM, and Schwartzberg PL. (2012) Positive and negative signaling through SLAM receptors regulate synapse organization and thresholds of cytolysis. Immunity 36(6):1003-16.