Most iNKT cells are CD1d restricted and recognize the synthetic glycolipid ligand α-galactosylceramide (α-GalCer). Therefore, this cell population can be identified using CD1d tetramers loaded with α-GalCer and antibodies specific for the T-cell receptor β-chain (TCRβ). Using this method, Mi et al. examined the number of iNKT cells in Aire−/− mice and found considerably fewer iNKT cells in the spleen, thymus, liver and bone marrow of these mice than in wild-type mice. Consistent with this, proliferation of thymocytes from Aire−/− mice was reduced following stimulation with α-GalCer. Therefore, the development of iNKT cells is defective in Aire−/− mice. The authors also showed that the percentage of mature (CD44hiNK1.1+(natural-killer-cell-associated antigen 1.1)) and intermediate (CD44hiNK1.1−) iNKT cells was markedly lower in both Aire−/− and Aire+/− mice than in wild-type mice, whereas the percentage of CD44lowNK1.1− immature iNKT cells was increased. This indicates that the maturation of iNKT cells is also severely affected in AIRE-deficient mice.
Next, through the use of reciprocal bone-marrow transfer, the authors showed that the influence of AIRE on iNKT-cell development is not through a defect in bone-marrow-derived cells, including CD4+CD8+ thymocytes that positively select iNKT cells. However, the expression of AIRE by thymic stromal cells is crucial for the development and maturation of iNKT cells. The ability of thymic stromal cells from Aire −/− mice to present α-GalCer to iNKT-cell hybridomas was greatly reduced, which might contribute to the important role of these cells in the development and maturation of iNKT cells.
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