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Premature Expression of Chemokine Receptor CCR9 Impairs T Cell Development

Shoji Uehara^*, Sandra M. Hayes^*, LiQi Li^*, Dalal El-Khoury^*, Matilde Canelles, B. J. Fowlkes and Paul E. Love^1,*

^* Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, and Laboratory of Molecular and Cellular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

During thymocyte development, CCR9 is expressed on late CD4^–CD8^– (double-negative (DN)) and CD4⁺CD8⁺ (double-positive) cells, but is subsequently down-regulated as cells transition to the mature CD4⁺ or CD8⁺ (single-positive (SP)) stage. This pattern of expression has led to speculation that CCR9 may regulate thymocyte trafficking and/or export. In this study, we generated transgenic mice in which CCR9 surface expression was maintained throughout T cell development. Significantly, forced expression of CCR9 on mature SP thymocytes did not inhibit their export from the thymus, indicating that CCR9 down-regulation is not essential for thymocyte emigration. CCR9 was also expressed prematurely on immature DN thymocytes in CCR9 transgenic mice. Early expression of CCR9 resulted in a partial block of development at the DN stage and a marked reduction in the numbers of double-positive and SP thymocytes. Moreover, in CCR9-transgenic mice, CD25^high DN cells were scattered throughout the cortex rather than confined to the subcapsular region of the thymus. Together, these results suggest that regulated expression of CCR9 is critical for normal development of immature thymocytes, but that down-regulation of CCR9 is not a prerequisite for thymocyte emigration.

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