IMPAIRED VIABILITY AND PROFOUND BLOCK IN THYMOCYTE DEVELOPMENT IN MICE LACKING THE ADAPTER PROTEIN SLP-76

The adaptor protein SLP-76 is expressed in T lymphocytes and myeloid c ells and is a substrate for ZAP-70 and Syk. We generated a SLP-76 null mutation in mice by homologous recombination in embryonic stem cells to evaluate the role of SLP-76 in T cell development and activation. S LP-76-deficient mice exhibited subcutaneous and intraperitoneal hemorr haging and impaired viability. Analysis of lymphoid cells revealed a p rofound block in thymic development with absence of double-positive CD 4(+)8(+) thymocytes and of peripheral T cells. This block could not be overcome by in vivo treatment with anti-CD3. V-D-J rearrangement of t he TCR beta locus was not obviously affected. B cell development was n ormal. These results indicate that SLP-76 collects all pre-TCR signals that drive the development and expansion of double-positive thymocyte s.