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CD8 Expression Up to the Double-Positive CD3^{Low/Intermediate} Stage of Thymic Differentiation Is Sufficient for Development of Peripheral Functional Cytotoxic T Lymphocytes

Correspondence to: J.W. Chamberlain, Research Institute, Programs in Infection, Immunity, Injury and Repair, and Genetics, The Hospital For Sick Children, Toronto, Ontario M5G 1X8, Canada. Tel:416-813-8323 Fax:416-813-8168 E-mail:jchamber{at}sickkids.on.ca.

Control of CD8 transcription during development of /ß T cell receptor (TCR) T lymphocytes is mediated by at least two distinct stage-specific cis-acting transcriptional mechanisms (i.e., enhancers). On the CD8^-/-knockout (KO) background, cis-mechanism I and cis-mechanism II together mediate appropriate stage- and sublineage-specific transgenic (Tg) CD8 expression and "rescue" development of peripheral CD8⁺ single-positive (SP) cytotoxic T lymphocytes (CTLs). In contrast, on the wild-type (WT)/CD8^+/+ or CD8^-/-KO backgrounds, a CD8 Tg directed by cis-mechanism I alone is activated during the double negative [DN] to double positive [DP] transition and expressed up to the CD3^{low/intermediate} DP stage but not in more mature DP or SP thymocytes or peripheral T cells. As loss of cis mechanism I activity occurs around the onset of positive selection, it is possible that events associated with TCR/major histocompatibility complex (MHC) interactions and selection are involved in initiating these changes in CD8 transcription. To examine this issue, phenotypic and functional studies were performed for thymocytes and T cells of CD8^-/-KO mice that expressed a CD8 Tg under control of cis-mechanism I only. Despite loss of CD8 expression at the DP CD3^{low/intermediate} stage, increased populations of mature CD3^hiCD4^-CD8^- thymocytes and CD3⁺CD4^-CD8^- peripheral T cells were detected. By several criteria, including MHC class I–restricted antigen recognition, these cells have at least partially undergone positive and negative selection. Therefore, initiation of selection and sublineage commitment are determined before loss of cis-mechanism I–mediated control of CD8 transcription. Further, CD8 expression beyond the CD3^{low/intermediate} DP thymic stage is not essential for CTL development in vivo or function.

Key Words: CD8, gene expression, stage-specific regulation, thymic selection, sublineage commitment

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• Cheuk, E., D'Souza, C., Hu, N., Liu, Y., Lang, H., Chamberlain, J. W. (2002). Human MHC Class I Transgenic Mice Deficient for H2 Class I Expression Facilitate Identification and Characterization of New HLA Class I-Restricted Viral T Cell Epitopes. J. Immunol. 169: 5571-5580 [Abstract] [Full Text]  

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