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
U2 - 10.4049/jimmunol.176.7.3958
DO - 10.4049/jimmunol.176.7.3958
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 -