The Journal of Experimental Medicine
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Published 16 June 2003. doi:10.1084/jem.20030170
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© Rockefeller University Press, 0022-1007/2003/6/1709 $5.00
The Journal of Experimental Medicine, Volume 197, Number 12, 1709-1719

Unraveling a Revealing Paradox : Why Major Histocompatibility Complex I–signaled Thymocytes "Paradoxically" Appear as CD4+8lo Transitional Cells During Positive Selection of CD8+ T Cells



Remy Bosselut1, Terry I. Guinter2, Susan O. Sharrow2 and Alfred Singer2

1 Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
2 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Alfred Singer, Experimental Immunology Branch, National Cancer Institute, Building 10, Room 4B36, Bethesda, MD 20892. Phone: 301-496-5461; Fax: 301-496-0887; E-mail: singera{at}nih.gov

The mechanism by which T cell receptor specificity determines the outcome of the CD4/CD8 lineage decision in the thymus is not known. An important clue is the fact that major histocompatibility complex (MHC)-I–signaled thymocytes paradoxically appear as CD4+8lo transitional cells during their differentiation into CD8+ T cells. Lineage commitment is generally thought to occur at the CD4+8+ (double positive) stage of differentiation and to result in silencing of the opposite coreceptor gene. From this perspective, the appearance of MHC-I–signaled thymocytes as CD4+8lo cells would be due to effects on CD8 surface protein expression, not CD8 gene expression. But contrary to this perspective, this study demonstrates that MHC-I–signaled thymocytes appear as CD4+8lo cells because of transient down-regulation of CD8 gene expression, not because of changes in CD8 surface protein expression or distribution. This study also demonstrates that initial cessation of CD8 gene expression in MHC-I–signaled thymocytes is not necessarily indicative of commitment to the CD4+ T cell lineage, as such thymocytes retain the potential to differentiate into CD8+ T cells. These results challenge classical concepts of lineage commitment but fulfill predictions of the kinetic signaling model.

Key Words: lineage commitment • kinetic signaling • coreceptor reversal • positive selection


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