During T cell development, interaction of the T cell receptor (TCR) with cognate ligands in the thymus may result in either maturation (positive selection) or death (negative selection). The intracellular pathways that control these opposed outcomes are not well characterized. We have generated mice expressing dominant-negative Ras (dnRas) and Mek-1 (dMek) transgenes simultaneously, either in otherwise normal animals, or in animals expressing a transgenic TCR, thereby permitting a comprehensive analysis of peptide-specific selection. In this system, thymocyte maturation beyond the CD4+8+ stage is blocked almost completely, whereas negative selection, assessed using an in vitro deletion protocol, is quantitatively intact. This suggests that activation of the mitogen-activated protein kinase (MAPK) cascade is necessary for positive selection, but irrelevant for negative selection. Generation of gamma/delta and of CD4-8- alpha/beta T cells proceeds normally despite blockade of the MAPK cascade. Hence, only cells that mature via conventional, TCR-mediated repertoire selection require activation of the MAPK pathway to complete their maturation.
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July 01 1996
Positive and negative selection invoke distinct signaling pathways.
J Alberola-Ila,
J Alberola-Ila
Howard Hughes Medical Institute, Seattle, Washington, USA.
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K A Hogquist,
K A Hogquist
Howard Hughes Medical Institute, Seattle, Washington, USA.
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K A Swan,
K A Swan
Howard Hughes Medical Institute, Seattle, Washington, USA.
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M J Bevan,
M J Bevan
Howard Hughes Medical Institute, Seattle, Washington, USA.
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R M Perlmutter
R M Perlmutter
Howard Hughes Medical Institute, Seattle, Washington, USA.
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J Alberola-Ila
Howard Hughes Medical Institute, Seattle, Washington, USA.
K A Hogquist
Howard Hughes Medical Institute, Seattle, Washington, USA.
K A Swan
Howard Hughes Medical Institute, Seattle, Washington, USA.
M J Bevan
Howard Hughes Medical Institute, Seattle, Washington, USA.
R M Perlmutter
Howard Hughes Medical Institute, Seattle, Washington, USA.
Online ISSN: 1540-9538
Print ISSN: 0022-1007
J Exp Med (1996) 184 (1): 9–18.
Citation
J Alberola-Ila, K A Hogquist, K A Swan, M J Bevan, R M Perlmutter; Positive and negative selection invoke distinct signaling pathways.. J Exp Med 1 July 1996; 184 (1): 9–18. doi: https://doi.org/10.1084/jem.184.1.9
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