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 journalArticlepeer-review

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
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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