| Abstract: |
The adaptor protein, downstream of tyrosine kinases-1 (Dok-1), and the phosphatase SHIP are both tyrosine phosphorylated in response to T cell stimulation. However, a function for these molecules in T cell development has not been defined. To clarify the role of Dok-1 and SHIP in T cell development in vivo, we compared the T cell phenotype of wild-type, Dok-1 knockout (KO), SHIP KO, and Dok-1/SHIP double-knockout (DKO) mice. Dok-1/SHIP DKO mice were runted and had a shorter life span compared with either Dok-1 KO or SHIP KO mice. Thymocyte numbers from Dok-1/SHIP DKO mice were reduced by 90%. Surface expression of both CD25 and CD69 was elevated on freshly isolated splenic CD4+ T cells from SHIP KO and Dok-1/SHIP DKO, suggesting these cells were constitutively activated. However, these T cells did not proliferate or produce IL-2 after stimulation. Interestingly, the CD4+ T cells from SHIP KO and Dok-1/SHIP DKO mice produced higher levels of TGF-β, expressed Foxp3, and inhibited IL-2 production by CD3-stimulated CD4+CD25 - T cells in vitro. These findings suggest Dok-1 and SHIP function in pathways that influence regulatory T cell development. Copyright © 2006 by The American Association of Immunologists, Inc. |
| Keywords: |
signal transduction; controlled study; protein expression; protein phosphorylation; survival rate; unclassified drug; dna binding protein; genetics; dna-binding proteins; nonhuman; protein function; transcription factor foxp3; antigen expression; lymphocyte proliferation; biological marker; biological markers; animal cell; mouse; phenotype; animal; cytology; metabolism; mouse mutant; animals; mice; mice, knockout; animal tissue; cells, cultured; interleukin 2; spleen; phosphatase; transforming growth factor beta; animal experiment; animal model; cell differentiation; in vitro study; enzymology; pathology; protein tyrosine kinase; rna binding protein; gene expression regulation; rna-binding proteins; lymphocyte differentiation; cd4+ cd25+ t lymphocyte; regulatory t lymphocyte; immunology; lymphocyte activation; cell culture; splenomegaly; cd4+ t lymphocyte; cd4-positive t-lymphocytes; phosphoproteins; cytokine production; cd4 antigen; phosphoric monoester hydrolases; phosphoprotein; t lymphocyte activation; protein tyrosine phosphatase shp 1; knockout mouse; interleukin 2 receptor alpha; lifespan; cell surface; interleukin 2 receptor; receptors, interleukin-2; adaptor protein; dok 1 protein; inositol 5' phosphatase; protein sh2; protein tyrosine kinase 1; dok1 protein, mouse; inppl1 protein, human
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