Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5'-phosphatase are required for regulation of CD4+CD25+ T cell development

Masaki Kashiwada; Giorgio Cattoretti; Lisa McKeag; Todd Rouse; Brian M Showalter; Umaima Al-Alem; Masaru Niki; Pier Paolo Pandolfi; Elizabeth H Field; Paul B Rothman

doi:10.4049/jimmunol.176.7.3958

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Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5'-phosphatase are required for regulation of CD4+CD25+ T cell development

Journal article

Open access

Peer reviewed

Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5'-phosphatase are required for regulation of CD4+CD25+ T cell development

Masaki Kashiwada, Giorgio Cattoretti, Lisa McKeag, Todd Rouse, Brian M Showalter, Umaima Al-Alem, Masaru Niki, Pier Paolo Pandolfi, Elizabeth H Field and Paul B Rothman

The Journal of immunology (1950), Vol.176(7), pp.3958-3965

04/01/2006

DOI: 10.4049/jimmunol.176.7.3958

PMID: 16547230

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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-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.

RNA-Binding Proteins - genetics

Phosphoric Monoester Hydrolases - deficiency

CD4-Positive T-Lymphocytes - enzymology

Splenomegaly - pathology

Phosphoproteins - metabolism

DNA-Binding Proteins - deficiency

CD4-Positive T-Lymphocytes - immunology

DNA-Binding Proteins - metabolism

Cell Differentiation

Phosphoric Monoester Hydrolases - genetics

Splenomegaly - genetics

Lymphocyte Activation

CD4-Positive T-Lymphocytes - cytology

Cells, Cultured

Gene Expression Regulation

Receptors, Interleukin-2 - metabolism

Survival Rate

Phosphoproteins - genetics

Splenomegaly - metabolism

DNA-Binding Proteins - genetics

Mice, Knockout

Phenotype

Animals

Phosphoproteins - deficiency

Biomarkers

Mice

Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases

Phosphoric Monoester Hydrolases - metabolism

RNA-Binding Proteins - metabolism

Details

Title: Subtitle: Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5'-phosphatase are required for regulation of CD4+CD25+ T cell development
Creators: Masaki Kashiwada - Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Giorgio Cattoretti
Lisa McKeag
Todd Rouse
Brian M Showalter
Umaima Al-Alem
Masaru Niki
Pier Paolo Pandolfi
Elizabeth H Field
Paul B Rothman
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.176(7), pp.3958-3965
DOI: 10.4049/jimmunol.176.7.3958
PMID: 16547230
ISSN: 0022-1767
eISSN: 1550-6606
Grant note: P01 AI50514 / NIAID NIH HHS CA-64593 / NCI NIH HHS R01 AI54821 / NIAID NIH HHS
Language: English
Date published: 04/01/2006
Academic Unit: Immunology; Internal Medicine
Record Identifier: 9984094702702771

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