Pediatric Rheumatology Online Journal → August 2003 →  Basic Immunology  → Abstract #167

SRC-LIKE ADAPTOR PROTEIN (SLAP), A NEGATIVE REGULATOR OF LYMPHOCYTE SIGNALING, PLAYS A ROLE IN B-CELL DEVELOPMENT AND MATURATION

L. L. Dragone,^1,2 T. Sosinowski,^2,3 A. Weiss.^2,3

¹Department of Pediatrics Division of Pediatric Immunology/Rheumatology, University of California San Francisco, San Francisco, CA, United States; ²Howard Hughes Medical institute, University of California San Francisco, San Francisco, CA, United States; ³Department of Medicine Division of Rheumatology, University of California San Francisco, San Francisco, CA, United States

A diverse repertoire of T and B-lymphocytes enables us to respond to a wide variety of environmental pathogens. Strength of signaling via the T- cell (TCR) or B- cell (BCR) antigen receptors determines the fate of that lymphocyte. Alterations in the strength of signaling through the antigen receptor may disrupt the balance between tolerance and immunity during an immune response. Both the intrinsic affinity and surface density of the antigen receptor contributes to its avidity for antigen. This avidity regulates strength of signaling within the cell. Recently, the src-like adaptor protein (SLAP), a regulator of antigen receptor density, has been identified. SLAP-deficient mice developed in our laboratory exhibit increased TCR expression levels on double positive (DP) thymocytes resulting in abnormal thymic selection. SLAP is also expressed in naive peripheral B cells, down-regulated upon BCR activation, and maintained in anergized B cells. We hypothesize that this regulated expression of SLAP in B cells will be important in modulating signals during times of B-cell activation or tolerance induction. To test this hypothesis we bred the SLAP deficient mice into a BCR transgenic system. This system utilizes two transgenic lines that express either a BCR specific for hen-egg lysozyme (HEL) or HEL as a soluble neo-self antigen. SLAP deficiency in this system leads to alterations in B cell maturation. HEL specific Ig levels are elevated in SLAP deficient BCR transgenic mice compared to controls suggesting a lower threshold for antibody secretion. In addition, the SLAP deficient BCR transgenic splenic B-cells have a IgM^low and heat stable antigen(HSA)^low phenotype compared to controls, suggesting increased signaling in the immature B cell pool. Given these data we suggest that SLAP deficiency leads to a decreased BCR signaling threshold resulting in a hyper-responsive B cell pool and alterations in B-cell maturation.