Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5'-phosphatase are required for regulation of CD4+CD25+ T cell development.
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-beta, 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.
Kashiwada
Masaki
M
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Cattoretti
Giorgio
G
McKeag
Lisa
L
Rouse
Todd
T
Showalter
Brian M
BM
Al-Alem
Umaima
U
Niki
Masaru
M
Pandolfi
Pier Paolo
PP
Field
Elizabeth H
EH
Rothman
Paul B
PB
D000818:Animals; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D013163:Splenomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate
D015415:Biomarkers; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D015375:Receptors, Interleukin-2; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases