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* Division of Basic Sciences, Immunobiology Working Group, Fox Chase Cancer Center, Philadelphia, PA 19111;
Department of Immunology, University of Toronto, Sunnybrook & Women’s College Health Sciences Center, Toronto, Ontario, Canada;
PROCREA BioSciences Inc., Montréal, Québec, Canada
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
subunit restores development of pT-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 
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 Ca2+ 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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