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Chain Selection of Fetal Murine Thymocytes
By
From the Max-Planck-Institut für Immunbiologie, 79108 Freiburg, Germany
After productive rearrangement of a TCR
chain gene, CD4
8 double negative (DN) thymocytes express TCR polypeptide chains on the cell surface together with pre-T
and the
CD3 complex forming the pre-TCR. Signals transmitted through the pre-TCR select
TCR+ DN thymocytes for further maturation to the CD4+8+ double positive stage, whereas
DN cells that fail to generate a productive TCR gene rearrangement do not continue in development. This process is termed TCR chain selection. Although it is likely that differences
between proliferation dynamics of TCR+ and TCR cells may play a role, the exact mechanisms of TCR chain selection have not been elucidated. We therefore studied the proliferation dynamics of TCR+ and TCR thymocytes during fetal development, i.e., when
TCR chain selection takes place for the first time. We analyzed in situ accumulation of
TCR+ thymocytes by confocal microscopy, and determined cell cycle and division parameters of TCR+ and TCR populations by flow cytometry. About 600 TCR+ cells/thymic
lobe are generated by independent induction events between days of gestation (dg) 13.5. and
15.5. As of dg 14.5, most TCR+ cells have entered S/G2 phase of cell cycle, followed by
seven to eight rapid cell divisions in fetal thymic organ culture, suggesting a corresponding
burst of nine cell divisions within 4 d in vivo. By dg 18.5, the division rate of TCR+ cells has
slowed down to less than 1/d. About three quarters of TCR cells divide at a slow rate of 1/d
on dg 14.5, the proportion of nondividing cells increasing to 50% within the following four d.
From dg 16.5 onwards, TCR cells, but not TCR+ cells, contain a significant proportion
of apoptotic cells. The results suggest that failure to become selected results in shutdown of
proliferation and eventual programmed cell death of fetal TCR cells. Positive selection of
fetal TCR+ cells is achieved by an increased rate of cell divisions lasting for approximately 4 d.
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