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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 Development¹

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^2,*,

^* Department of Medicine and Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242; Veterans Affairs Medical Center, Iowa City, IA 52246; and ^¶ Department of Human Genetics, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

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-, 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.

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