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Distinct Stage-Specific cis-Active Transcriptional Mechanisms Control Expression of T Cell Coreceptor CD8 at Double- and Single-Positive Stages of Thymic Development¹

Xiao-Li Zhang^*, Rho Seong^2,, Rafia Piracha^*, Mani Larijani^*, Matthew Heeney^*, Jane R. Parnes and John W. Chamberlain^3,*

^* Research Institute, Hospital For Sick Children, and Department of Immunology, University of Toronto, Toronto, Ontario, Canada; and Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305

Developing thymocytes that give rise to CD8⁺ (cytotoxic) and CD4⁺ (helper) ß-TCR T lymphocytes go through progressive stages of expression of coreceptors CD8 and CD4 from being negative for both (the double-negative stage), to coexpressing both (the double-positive (DP) stage), to a mutually exclusive sublineage-specific expression of one or the other (the single-positive (SP) stage). To delineate the mechanisms underlying regulation of CD8 during these developmental transitions, we have examined expression of a series of mouse CD8 gene constructs in developing T cells of conventional and CD8 "knock-out" transgenic mice. Our results indicate that cis-active transcriptional control sequences essential for stage- and sublineage-specific expression lie within a 5' 40-kb segment of the CD8 locus, 12 kb upstream of the CD8 gene. Studies to characterize and sublocalize these cis sequences showed that a 17-kb 5' subfragment is able to direct expression of the CD8 gene up to the CD3^intermediate DP stage but not in more mature DP or SP cells. These results indicate that stage-specific expression of CD8 in developing T cells is mediated by the differential activity of multiple functionally distinct cis-active transcriptional control mechanisms. It will be important to determine the relationship of "switching" between these cis mechanisms and selection.

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