Aberrant T-cell ontogeny and defective thymocyte and colonic T-cell chemotactic migration in colitis-prone Gαi2-deficient mice

摘要

Gαi2-deficient mice, which spontaneously develop colitis, have previously been reported to have an increased frequency of mature, single positive thymocytes compared to wild-type mice. In this study we further characterized the intrathymic changes in these mice before and during overt colitis. Even before the onset of colitis, Gαi2^–/– thymi weighed less and contained fewer thymocytes, and this was exacerbated with colitis development. Whereas precolitic Gαi2^–/– mice had unchanged thymocyte density compared to Gαi2^+/– mice of the same age, this was significantly decreased in mice with colitis. Thymic atrophy in Gαi2^–/– mice involved mainly the cortex. Using a five-stage phenotypic characterization of thymocyte maturation based on expression of CD4, CD8, TCRαβ, CD69 and CD62L, we found that both precolitic and colitic Gαi2^–/– mice had significantly increased frequencies of mature single-positive CD4⁺ and CD8⁺ medullary thymocytes, and significantly reduced frequencies and total numbers of immature CD4⁺ CD8⁺ double-positive thymocytes compared to Gαi2^+/– mice. Furthermore, cortical and transitional precolitic Gαi2^–/– thymocytes showed significantly reduced chemotactic migration towards CXCL12, and a trend towards reduced migration to CCL25, compared to wild-type thymocytes, a feature even more pronounced in colitic mice. This impaired chemotactic migration of Gαi2^–/– thymocytes could not be reversed by increased chemokine concentrations. Gαi2^–/– thymocytes also showed reduced expression of the CCL25 receptor CCR9, but not CXCR4, the receptor, for CXCL12. Finally, wild-type colonic lamina propria lymphocytes migrated in response to CXCL12, but not CCL25 and, as with thymocytes, the chemokine responsiveness was significantly reduced in Gαi2^–/– mucosal lymphocytes.