Abstract
NOD (non-obese diabetic) mice spontaneously develop type 1 diabetes following T cell-dependent destruction of pancreatic β cells. Several alterations are observed in the NOD thymus, including the presence of giant perivascular spaces (PVS) filled with single-positive (SP) CD4+ and CD8+ T cells that accumulate in the organ. These cells have a decreased expression of membrane CD49e (the α5 integrin chain of the fibronectin receptor VLA-5 (very late antigen-5). Herein, we observed lower sphingosine-1-phosphate receptor 1 (S1P1) expression in NOD mouse thymocytes when compared with controls, mainly in the mature SP CD4+CD62Lhi and CD8+CD62Lhi subpopulations bearing the CD49e− phenotype. In contrast, differences in S1P1 expression were not observed in mature CD49e+ thymocytes. Functionally, NOD CD49e− thymocytes had reduced S1P-driven migratory response, whereas CD49e+ cells were more responsive to S1P. We further noticed a decreased expression of the sphingosine-1-phosphate lyase (SGPL1) in NOD SP thymocytes, which can lead to a higher sphingosine-1-phosphate (S1P) expression around PVS and S1P1 internalization. In summary, our results indicate that the modulation of S1P1 expression and S1P/S1P1 interactions in NOD mouse thymocytes are part of the T-cell migratory disorder observed during the pathogenesis of type 1 diabetes.
Highlights
NOD mice spontaneously develop type I diabetes (T1D) as a result of the autoreactive destruction of the insulin-producing β cells in the pancreatic islets
The formation of giant perivascular spaces (PVS) in the NOD thymus seems to result from a progressive accumulation of mature T cells, as in vivo experiments showed similar rates of fluorescein isothiocyanate (FITC)-stained recent thymic emigrants in NOD peripheral lymphoid organs when compared with controls [7], indicating that other cell migration-related molecules could be involved in this process
NOD thymocytes have a decreased expression of S1P1 when compared with C57BL/6 thymocytes, and this is mainly observed in CD4+ and CD8+ SP subpopulations, in the more mature SP CD4+CD62Lhi and SP CD8+CD62Lhi subpopulations, which under normal conditions, are those ready to leave the organ [30]
Summary
NOD (non-obese diabetic) mice spontaneously develop type I diabetes (T1D) as a result of the autoreactive destruction of the insulin-producing β cells in the pancreatic islets. Giant PVS are filled with mature single-positive (SP) CD4+, CD8+ [5] and FoxP3+ regulatory T cells [6] These cells are reported to present a defect in the membrane expression of VLA-5 (very late antigen-5, the α5β1 integrin), a fibronectin receptor, suggesting the involvement of this molecule in thymocyte accumulation within the organ [6,7,8]. The formation of giant PVS in the NOD thymus seems to result from a progressive accumulation of mature T cells, as in vivo experiments showed similar rates of fluorescein isothiocyanate (FITC)-stained recent thymic emigrants in NOD peripheral lymphoid organs when compared with controls [7], indicating that other cell migration-related molecules could be involved in this process
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