TY - JOUR
T1 - Dysregulated expression of pre-Tα reveals the opposite effects of pre-TCR at successive stages of T cell development
AU - Lacorazza, H. D.
AU - Porritt, H. E.
AU - Nikolich-Žugich, J.
PY - 2001/11/15
Y1 - 2001/11/15
N2 - The pre-TCR complex (TCRβ-pre-TCRα chain (pTα)), first expressed in a fraction of CD8-4-CD44-25+ (DN3) cells, is believed to facilitate or enable an efficient transition from the CD8-4- double-negative (DN) to the CD8+4+ double-positive (DP) developmental stage. Subsequent to pre-TCR expression, DN3 thymocytes receive survival, proliferation, and differentiation signals, although it is still unclear which of these outcomes are directly induced by the pre-TCR. To address this issue, we generated mice bearing a range of ptα transgene copy number under the transcriptional control of the p56lck proximal promoter. All lines exhibited increased DN3 cycling, accelerated DN3/4 transition, and improved DN4 survival. However, the high copy number lines also showed a selective reduction in thymic cellularity due to increased apoptosis of DP thymocytes, which could be reversed by the ectopic expression of Bcl-2. Our results suggest that transgenic ptα likely caused apoptosis of DP thymocytes due to competitive decrease in surface TCRαβ formation. These results highlight the critical importance of precise temporal and stoichiometric regulation of pre-TCR and TCR component expression.
AB - The pre-TCR complex (TCRβ-pre-TCRα chain (pTα)), first expressed in a fraction of CD8-4-CD44-25+ (DN3) cells, is believed to facilitate or enable an efficient transition from the CD8-4- double-negative (DN) to the CD8+4+ double-positive (DP) developmental stage. Subsequent to pre-TCR expression, DN3 thymocytes receive survival, proliferation, and differentiation signals, although it is still unclear which of these outcomes are directly induced by the pre-TCR. To address this issue, we generated mice bearing a range of ptα transgene copy number under the transcriptional control of the p56lck proximal promoter. All lines exhibited increased DN3 cycling, accelerated DN3/4 transition, and improved DN4 survival. However, the high copy number lines also showed a selective reduction in thymic cellularity due to increased apoptosis of DP thymocytes, which could be reversed by the ectopic expression of Bcl-2. Our results suggest that transgenic ptα likely caused apoptosis of DP thymocytes due to competitive decrease in surface TCRαβ formation. These results highlight the critical importance of precise temporal and stoichiometric regulation of pre-TCR and TCR component expression.
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U2 - 10.4049/jimmunol.167.10.5689
DO - 10.4049/jimmunol.167.10.5689
M3 - Article
C2 - 11698441
AN - SCOPUS:0035889891
SN - 0022-1767
VL - 167
SP - 5689
EP - 5696
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -