TY - JOUR
T1 - Positive and negative selection invoke distinct signaling pathways
AU - Alberola-Ila, José
AU - Hogquist, Kristin A.
AU - Swan, Kathryn A.
AU - Bevan, Michael J.
AU - Perlmutter, Roger M.
PY - 1996/7/1
Y1 - 1996/7/1
N2 - 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 γ/δ and of CD4-8- α/β 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.
AB - 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 γ/δ and of CD4-8- α/β 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.
UR - http://www.scopus.com/inward/record.url?scp=0030018912&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030018912&partnerID=8YFLogxK
U2 - 10.1084/jem.184.1.9
DO - 10.1084/jem.184.1.9
M3 - Article
C2 - 8691153
AN - SCOPUS:0030018912
SN - 0022-1007
VL - 184
SP - 9
EP - 18
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 1
ER -