Mechanistic basis of pre–T cell receptor–mediated autonomous signaling critical for thymocyte development

Sho Yamasaki¹, Eri Ishikawa¹, Machie Sakuma¹, Koji Ogata², Kumiko Sakata-Sogawa³, Michio Hiroshima³, David L Wiest⁴, Makio Tokunaga^3, 5 & Takashi Saito¹

¹  Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.

²  Centre for Computational Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.

³  Single Molecule Immunoimaging, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.

⁴  Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

⁵  Structural Biology Center, National Institute of Genetics, and Department of Genetics, The Graduate University for Advanced Studies, Shizuoka 411-8540, Japan.

The pre–T cell receptor (TCR) is crucial for early T cell development and is proposed to function in a ligand-independent way. However, the molecular mechanism underlying the autonomous signals remains elusive. Here we show that the pre-TCR complex spontaneously formed oligomers. Specific charged residues in the extracellular domain of the pre-TCR -chain mediated formation of the oligomers in vitro. Alteration of these residues eliminated the ability of the pre-TCR -chain to support pre-TCR signaling in vivo. Dimerization but not raft localization of CD3 was sufficient to simulate pre-TCR function and promote -selection. These results suggest that the pre-TCR complex can deliver its signal autonomously through oligomerization of the pre-TCR -chain mediated by charged residues.

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