The Journal of Experimental Medicine
ThymUS '08
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Published online 26 March 2001.
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© The Rockefeller University Press, 0022-1007/2001/4/815/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 7, April 2, 2001 815-826

Original Article

Autonomous Maturation of {alpha}/ß T Lineage Cells in the Absence of COOH-terminal Src Kinase (Csk)

Christian Schmedta,b and Alexander Tarakhovskya,b
a Laboratory for Lymphocyte Signaling, The Rockefeller University, New York, New York 10021
b Laboratory for Lymphocyte Signaling, Institute for Genetics, University of Cologne, 50931 Cologne, Germany

Correspondence to: Christian Schmedt, Laboratory for Lymphocyte Signaling, The Rockefeller University, Box 301, 1230 York Ave., New York, NY 10021. Tel:212-327-8265 Fax:212-327-8258 E-mail:schmedc{at}mail.rockefeller.edu.

The deletion of COOH-terminal Src kinase (Csk), a negative regulator of Src family protein tyrosine kinases (PTKs), in immature thymocytes results in the development of {alpha}/ß T lineage cells in T cell receptor (TCR) ß-deficient or recombination activating gene (rag)-1–deficient mice. The function of Csk as a repressor of Lck and Fyn activity suggests activation of these PTKs is solely responsible for the phenotype observed in csk-deficient T lineage cells. We provide genetic evidence for this notion as {alpha}/ß T cell development is blocked in lck-/-fyn-/- csk-deficient mice. It remains unclear whether activation of Lck and Fyn in the absence of Csk uncouples {alpha}/ß T cell development entirely from engagement of surface-expressed receptors. We show that in mice expressing the {alpha}/ß TCR on csk-deficient thymocytes, positive selection is biased towards the CD4 lineage and does not require the presence of major histocompatibility complex (MHC) class I and II. Furthermore, the introduction of an MHC class I–restricted transgenic TCR into a csk-deficient background results in the development of mainly CD4 T cells carrying the transgenic TCR both in selecting and nonselecting MHC background. Thus, TCR–MHC interactions have no impact on positive selection and commitment to the CD4 lineage in the absence of Csk. However, TCR-mediated negative selection of csk-deficient, TCR transgenic cells is normal. These data suggest a differential involvement of the Csk-mediated regulation of Src family PTKs in positive and negative selection of developing thymocytes.

Key Words: thymocyte development, thymic selection, conditional gene targeting, T cell receptor, Src family kinases


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