Low activation threshold as a mechanism for ligand-independent signaling in pre-T cells |
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Authors: | Haks Mariëlle C Belkowski Stanley M Ciofani Maria Rhodes Michele Lefebvre Juliette M Trop Sebastién Hugo Patrice Zúñiga-Pflücker Juan Carlos Wiest David L |
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Affiliation: | Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. |
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Abstract: | Pre-TCR complexes are thought to signal in a ligand-independent manner because they are constitutively targeted to lipid rafts. We report that ligand-independent signaling is not a unique capability of the pre-TCR complex. Indeed, the TCR alpha subunit restores development of pT alpha-deficient thymocytes to the CD4(+)CD8(+) stage even in the absence of conventional MHC class I and class II ligands. Moreover, we found that pre-TCR and alpha beta TCR complexes exhibit no appreciable difference in their association with lipid rafts, suggesting that ligand-independence is a function of the CD4(-)CD8(-) (DN) thymocytes in which pre-TCR signaling occurs. In agreement, we found that only CD44(-)CD25(+) DN thymocytes (DN3) enabled activation of extracellular signal-regulated kinases by the pre-TCR complex. DN thymocytes also exhibited a lower signaling threshold relative to CD4(+)CD8(+) thymocytes, which was associated with both the markedly elevated lipid raft content of their plasma membranes and more robust capacitative Ca(2+) entry. Taken together these data suggest that cell-autonomous, ligand-independent signaling is primarily a property of the thymocytes in which pre-TCR signaling occurs. |
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