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*
Institute of Virology and Immunobiology, Würzburg, Germany; and
Division of Molecular Immunology, National Institute for Medical Research, London, United Kingdom
CD4+CD8+ thymocytes are either positively
selected and subsequently mature to CD4 single positive (SP) or CD8 SP
T cells, or they die by apoptosis due to neglect or negative selection.
This clonal selection is essential for establishing a functional
self-restricted T cell repertoire. Intracellular signals through the
three known mitogen-activated protein (MAP) kinase pathways have been
shown to selectively guide positive or negative selection. Whereas the
c-Jun N-terminal kinase and p38 MAP kinase regulate negative selection
of thymocytes, the extracellular signal-regulated kinase (ERK) pathway
is required for positive selection and T cell lineage commitment. In
this paper, we show that the MAP/ERK kinase (MEK)-ERK pathway is also
involved in negative selection. Thymocytes from newborn TCR transgenic
mice were cultured with TCR/CD3
-specific Abs or TCR-specific agonist
peptides to induce negative selection. In the presence of the
MEK-specific pharmacological inhibitors PD98059 or UO126, cell recovery
was enhanced and deletion of DP thymocytes was drastically reduced.
Furthermore, development of CD4 SP T cells was blocked, but
differentiation of mature CD8 SP T cells proceeded in the presence of
agonist peptides when MEK activity was blocked. Thus, our data indicate
that the outcome between positively and negatively selecting signals is
critically dependent on MEK activity.
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