Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76.
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.
Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
V
V
Pivniouk
E
E
Tsitsikov
P
P
Swinton
G
G
Rathbun
F W
FW
Alt
R S
RS
Geha
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001854:Bone Marrow Cells; D017252:CD3 Complex / Q000502:physiology; D002454:Cell Differentiation; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000235:genetics; D007694:Killer Cells, Natural; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000254:growth & development* / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D017252:CD3 Complex; D010750:Phosphoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; C092947:SLP-76 signal Transducing adaptor proteins