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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3958-3965
Number of pages8
JournalJournal of Immunology
Volume176
Issue number7
StatePublished - Apr 1 2006
Externally publishedYes

Fingerprint

src-Family Kinases
Protein-Tyrosine Kinases
T-Lymphocytes
Knockout Mice
Interleukin-2
Inositol Polyphosphate 5-Phosphatases
Regulatory T-Lymphocytes
Thymocytes
Tyrosine
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5′-phosphatase are required for regulation of CD4+CD25 + T cell development. / Kashiwada, Masaki; Cattoretti, Giorgio; McKeag, Lisa; Rouse, Todd; Showalter, Brian M.; Al-Alem, Umaima; Niki, Masaru; Pandolfi, Pier Paolo; Field, Elizabeth H.; Rothman, Paul B.

In: Journal of Immunology, Vol. 176, No. 7, 01.04.2006, p. 3958-3965.

Research output: Contribution to journalArticle

Kashiwada, M, Cattoretti, G, McKeag, L, Rouse, T, Showalter, BM, Al-Alem, U, Niki, M, Pandolfi, PP, Field, EH & Rothman, PB 2006, 'Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5′-phosphatase are required for regulation of CD4+CD25 + T cell development', Journal of Immunology, vol. 176, no. 7, pp. 3958-3965.
Kashiwada, Masaki ; Cattoretti, Giorgio ; McKeag, Lisa ; Rouse, Todd ; Showalter, Brian M. ; Al-Alem, Umaima ; Niki, Masaru ; Pandolfi, Pier Paolo ; Field, Elizabeth H. ; Rothman, Paul B. / Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5′-phosphatase are required for regulation of CD4+CD25 + T cell development. In: Journal of Immunology. 2006 ; Vol. 176, No. 7. pp. 3958-3965.
@article{64539d12e3604dc1a38df1c9544e4975,
title = "Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5′-phosphatase are required for regulation of CD4+CD25 + T cell development",
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.",
author = "Masaki Kashiwada and Giorgio Cattoretti and Lisa McKeag and Todd Rouse and Showalter, {Brian M.} and Umaima Al-Alem and Masaru Niki and Pandolfi, {Pier Paolo} and Field, {Elizabeth H.} and Rothman, {Paul B}",
year = "2006",
month = "4",
day = "1",
language = "English (US)",
volume = "176",
pages = "3958--3965",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "7",

}

TY - JOUR

T1 - Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5′-phosphatase are required for regulation of CD4+CD25 + T cell development

AU - Kashiwada, Masaki

AU - Cattoretti, Giorgio

AU - McKeag, Lisa

AU - Rouse, Todd

AU - Showalter, Brian M.

AU - Al-Alem, Umaima

AU - Niki, Masaru

AU - Pandolfi, Pier Paolo

AU - Field, Elizabeth H.

AU - Rothman, Paul B

PY - 2006/4/1

Y1 - 2006/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33646040440&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646040440&partnerID=8YFLogxK

M3 - Article

C2 - 16547230

AN - SCOPUS:33646040440

VL - 176

SP - 3958

EP - 3965

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 7

ER -