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Abstract
The adaptor protein SLP-76 is expressed in T lymphocytes and myeloid cells 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. SLP-76-deficient mice exhibited subcutaneous and intraperitoneal hemorrhaging
and impaired viability. Analysis of lymphoid cells revealed a profound block in thymic
development with absence of double-positive CD4+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 the TCRbeta locus was not obviously affected. B cell development
was normal. These results indicate that SLP-76 collects all pre-TCR signals that drive
the development and expansion of double-positive thymocytes.