The quantity of TCR signal determines positive selection and lineage commitment of T cells

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, particula rly in vivo. To address this issue, we analyzed DO-TCR transgenic CD3 zeta -deficient (DO-Tg/zeta KO) mice in which T tells have a reduced TCR on the cell surface. In DO-Tg/zeta KO mice, very few CD4 single positive (SP) thym ocytes 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/zeta KO mice resulted in the generation of functional CD4 SP mature thymocytes in a dose-dependent manner, and, unexpectedly, DO- Tg CDS SP cells emerged at lower doses of Ag, TCR signal-dependent, sequent ial commitment from CD8(+) SP to CD4(+) SP was also shown in a class I-rest ricted TCR-Tg system. These in vivo analyses demonstrate that the quantity of TCR signal directly determines positive and negative selection, and furt her suggest that weak signal directs positively selected T cells to CD8 lin eage and stronger signal to CD4 lineage.