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

Abstract

Summary 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.

Loss of Gαi proteins impairs thymocyte development, disrupts T-cell trafficking, and leads to an expanded population of splenic CD4+PD-1+CXCR5+/− T-cells

“…We did find that 6–12 week old Gnai2 −/− and Gnai2 fl/fl vav1-cre mice had visibly smaller thymuses than the controls. Others have reported fewer thymocytes in Gnai2 −/− mice post weaning 17 . Surprisingly, we did not find fewer ETPs in the Gnai2 fl/fl vav1-cre mice indicating that Gα i3 compensated for the loss of Gα i2 for entrance into the thymus.…”

Mechanisms of intestinal inflammation and development of associated cancers: Lessons learned from mouse models

“…Gαi2 -/- mice develop alterations in T cell maturation and function, including defective chemotactic migration of thymic and colonic T cells, which contributes to a Th1/Th17-driven colitis after 3-4 weeks of age and colorectal cancer within 3-4 months [112,174,175]. A defective epithelial barrier prior to clinically active inflammation and defective numbers and regulatory function of B cells in the mesenteric lymph nodes also have been observed, implicating both epithelial cells and immune cells in colitis development in this model [167].…”

CD4+FoxP3+ Regulatory T Cells from Gαi2−/− Mice Are Functionally Active In Vitro, but Do Not Prevent Colitis

“…The lack of Gαi2 results in functional disorders in epithelial cells [5], professional antigen-presenting cells [6], B cells [2], [4], [6] and CD4 + T cells [1], [3], [7], [8], [9] and points to multiple requirements for Gαi2 in mucosal immune regulation, but the underlying molecular mechanisms involving Gαi2 have not been defined.…”