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Degree of ERK activation influences both positive and negative thymocyte selection.
Mariathasan S; Ho SS; Zakarian A; Ohashi PS; Ontario Cancer Institute,
July 30, 2000
Eur J Immunol. 2000 Apr;30(4):1060-8. Unique Identifier : AIDSLINE

Considerable evidence suggests that the ERK pathway is required for positive but not negative thymocyte selection. Here, we report that ERK is highly activated in double-positive (DP) thymocytes expressing an MHC class I-restricted TCR (P14) in response to negatively selecting conditions, whereas ligands that trigger positive selection induced weaker ERK activation. Biochemical evidence also shows that death by neglect is associated with a further reduction in ERK activation. These findings are consistent with the affinity / avidity model of thymocyte selection. To further examine the role of ERK in negative selection we used the MEK-1 inhitibor, PD98059, a specific pharmacological inhibitor of the ERK pathway. Biochemical data demonstrated a reduction of ERK activity by PD98059 in the presence of the negatively selecting ligand. Analysis of P14 TCR-transgenic fetal thymic lobes cultured with PD98059 under negatively selecting conditions showed impaired clonal deletion of DP thymocytes and a concomitant increase in positive selection of functional mature, TCR(hi) transgenic T cells. This demonstrates that altering ERK activity switched negative to positive selection. Contrary to previous reports that show an exclusive role for ERK signaling in positive selection, our data demonstrate that negative selection is also sensitive to the degree of ERK activation.

JOURNAL ARTICLE Animal Cell Differentiation/DRUG EFFECTS Cell Division/DRUG EFFECTS Cell Lineage/DRUG EFFECTS Cell Survival/DRUG EFFECTS CD8-Positive T-Lymphocytes/DRUG EFFECTS/IMMUNOLOGY DNA-Binding Proteins/GENETICS/IMMUNOLOGY Enzyme Activation/DRUG EFFECTS Flavones/PHARMACOLOGY H-2 Antigens/GENETICS/IMMUNOLOGY Ligands Mice Mice, Transgenic Mitogen-Activated Protein Kinase Kinases/ANTAGONISTS & INHIB/ METABOLISM Mitogen-Activated Protein Kinases/ANTAGONISTS & INHIB/*METABOLISM MAP Kinase Signaling System/DRUG EFFECTS Organ Culture Peptides/PHARMACOLOGY Protein-Serine-Threonine Kinases/ANTAGONISTS & INHIB/METABOLISM Receptors, Antigen, T-Cell/IMMUNOLOGY Support, Non-U.S. Gov't T-Lymphocytes/*ENZYMOLOGY/*IMMUNOLOGY Thymus Gland/CYTOLOGY/DRUG EFFECTS/IMMUNOLOGY

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