| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 100 === The development of invariant NKT (iNKT) cells depends on the thymus. After positive selection by CD4+CD8+ CD1d+ cortical thymocytes, iNKT cells proceed from CD44lowNK1.1－ (stage 1) to CD44highNK1.1－ (stage 2), and then to CD44highNK1.1+ (stage 3) cells. The programming of cytokine production occurs along the three differentiation stages, whereas the acquisition of NK receptors occurs at stage 3. A great majority of stage 2 iNKT cells exit the thymus and complete differentiation in the peripheral organs to constitute the peripheral iNKT cell pool. In this study, we found that the number of iNKT cells reduced by more than 70% in the thymus, liver and bone marrow (BM), but remained normal in the spleen of Il15ra-/- (KO) mice. IL-15R of radiation-resistant thymic cells is necessary and sufficient for the homeostasis of thymic iNKT cells, whereas IL-15R of either BM-derived cells or radiation-resistant nonthymic cells regulated iNKT cell numbers in the BM and liver. Stage 3 thymic iNKT cells are specifically reduced in KO mice. We demonstrate that increased cell death contributed to the reduction of stage 3 cells in KO mice, as knockout of Bim restored this population. IL-15-dependent upregulation of Bcl-2 in stage 3 cells affected cell survival, as overexpression of hBcl-2 partially restored stage 3 cells in KO mice. Moreover, thymic iNKT cells in KO mice were impaired in functional maturation, including the acquisition of Ly49 and NKG2 receptors and the programming of cytokine production. Finally, IL-15Ra expressed by radiation-resistant cells is necessary and sufficient to support the survival as well as the examined maturation events of thymic iNKT cells.
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