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A Class I Transgene Reveals Regulatory Events on Chromosome 1 Marking Peripheral T Cell Differentiation and Memory¹

Cari Roark Sloma^*, Michael J. Hansen^*, Audrey A. MacDougall^*, Virginia P. Van Keulen^*, Robert B. Jenkins and Larry R. Pease^2,*

Departments of^* Immunology and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905

T cells respond to external signals by altering patterns of gene expression. Our characterization of a transgenic mouse revealed a genetic locus that is specifically regulated in T cells. Elucidation of the factors controlling the expression of the marker transgene may reveal basic regulatory mechanisms used by T cells as they differentiate from naive to primed/memory T cells. Although endogenous MHC class I K^q expression is normal in these animals, expression of the K^b transgene differentiates naive from primed/memory T cells. K^bHigh T cells bear the phenotypic and functional properties of primed/memory T cells, while K^bLow T cells have naive phenotypes. The transition from K^bLow to K^bHigh appears to involve signals resulting from engagement of the TCR. We show that transgene integration has occurred on chromosome 1, between D1Mit365 and D1Mit191. The gene regulatory mechanisms directing expression of the locus marked by the transgene are distinct from those controlling other known T cell-related genes within this locus. Stimulation of K^bHigh T cells results in the up-regulation of both the endogenous K^q gene and the K^b transgene. However, the same stimuli induce increased expression of only K^q on K^bLow T cells. This indicates that even though the transcription factors necessary for class I expression are present in K^bLow T cells, the K^b gene appears not to be accessible to these factors. These findings suggest a change in chromatin structure at the transgene integration site as cells progress from a naive to a primed/memory differentiation state.