title: Low activation threshold as a mechanism for ligand-independent signaling in pre-T cells.
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.
authors.affiliation: Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Mariëlle C
authors.initials: MC
authors.lastname: Haks
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Belkowski
authors.forename: Maria
authors.initials: M
authors.lastname: Ciofani
authors.forename: Michele
authors.initials: M
authors.lastname: Rhodes
authors.forename: Juliette M
authors.initials: JM
authors.lastname: Lefebvre
authors.forename: Sebastién
authors.initials: S
authors.lastname: Trop
authors.forename: Patrice
authors.initials: P
authors.lastname: Hugo
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
authors.forename: David L
authors.initials: DL
authors.lastname: Wiest
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009924:Organ Culture Techniques; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013234:Stem Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology / Q000276:immunology
chemical_list: D008024:Ligands; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C090377:pre-T cell receptor alpha; D020928:Mitogen-Activated Protein Kinases