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The Quantity of TCR Signal Determines Positive Selection and Lineage Commitment of T Cells¹

Norihiko Watanabe^*, Hisashi Arase^*, Makoto Onodera^*, Pamela S. Ohashi and Takashi Saito^2,*

^* Department of Molecular Genetics, Chiba University Graduate School of Medicine, Chiba, Japan; and Departments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario, Canada

It is generally accepted that the avidity of TCR for self Ag/MHC determines the fate of immature thymocytes. However, the contribution of the quantity of TCR signal to T cell selection has not been well established, particularly in vivo. To address this issue, we analyzed DO-TCR transgenic CD3-deficient (DO-Tg/KO) mice in which T cells have a reduced TCR on the cell surface. In DO-Tg/KO mice, very few CD4 single positive (SP) thymocytes developed, indicating that the decrease in TCR signaling resulted in a failure of positive selection of DO-Tg thymocytes. Administration of the peptide Ag to DO-Tg/KO mice resulted in the generation of functional CD4 SP mature thymocytes in a dose-dependent manner, and, unexpectedly, DO-Tg CD8 SP cells emerged at lower doses of Ag. TCR signal-dependent, sequential commitment from CD8⁺ SP to CD4⁺ SP was also shown in a class I-restricted TCR-Tg system. These in vivo analyses demonstrate that the quantity of TCR signal directly determines positive and negative selection, and further suggest that weak signal directs positively selected T cells to CD8 lineage and stronger signal to CD4 lineage.

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