Aberrant T-cell ontogeny and defective thymocyte and colonic T-cell chemotactic migration in colitis-prone Galphai2-deficient mice.
Galphai2-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, Galphai2(-/-) thymi weighed less and contained fewer thymocytes, and this was exacerbated with colitis development. Whereas precolitic Galphai2(-/-) mice had unchanged thymocyte density compared to Galphai2(+/-) mice of the same age, this was significantly decreased in mice with colitis. Thymic atrophy in Galphai2(-/-) mice involved mainly the cortex. Using a five-stage phenotypic characterization of thymocyte maturation based on expression of CD4, CD8, TCRalphabeta, CD69 and CD62L, we found that both precolitic and colitic Galphai2(-/-) 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 Galphai2(+/-) mice. Furthermore, cortical and transitional precolitic Galphai2(-/-) 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 Galphai2(-/-) thymocytes could not be reversed by increased chemokine concentrations. Galphai2(-/-) 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 Galphai2(-/-) mucosal lymphocytes.
Elgbratt
Kristina
K
Department of Microbiology and Immunology, Institute of Biomedicine, The Sahlgrenska Academy at Göteborg University, Sweden.
Bjursten
Malin
M
Willén
Roger
R
Bland
Paul W
PW
Hörnquist
Elisabeth Hultgren
EH
D000818:Animals; D054377:Chemokine CXCL12; D018925:Chemokines / Q000276:immunology; D019743:Chemokines, CXC / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000172:deficiency* / Q000235:genetics; D007413:Intestinal Mucosa / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D054388:Receptors, CCR; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology
C119309:CC chemokine receptor 9; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D054388:Receptors, CCR; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D051960:GTP-Binding Protein alpha Subunit, Gi2; C498016:Gnai2 protein, mouse