Positive and negative selection invoke distinct signaling pathways.
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.
Alberola-Ila
J
J
Howard Hughes Medical Institute, Seattle, Washington, USA.
Hogquist
K A
KA
Swan
K A
KA
Bevan
M J
MJ
Perlmutter
R M
RM
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D017931:DNA Primers / Q000737:chemistry; D048369:MAP Kinase Kinase 1; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D017931:DNA Primers; D010455:Peptides; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)