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 language | English (US) |
|---|---|
| Pages (from-to) | 3958-3965 |
| Number of pages | 8 |
| Journal | Journal of Immunology |
| Volume | 176 |
| Issue number | 7 |
| State | Published - Apr 1 2006 |
| Externally published | Yes |
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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 journal › Article
}
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.
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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 -