IL-15Rα of Radiation-Resistant Cells Is Necessary and Sufficient for Thymic Invariant NKT Cell Survival and Functional Maturation

Abstract

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. Stage 3 thymic iNKT cells are specifically reduced in Il15ra−/− mice. The mechanism underlying this homeostatic deficiency and whether the IL-15 system affects other thymic iNKT cell developmental events remain elusive. In this study, we demonstrate that increased cell death contributed to the reduction of stage 3 cells in Il15ra−/− 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 Il15ra−/− mice. Moreover, thymic iNKT cells in Il15ra−/− mice were impaired in functional maturation, including the acquisition of Ly49 and NKG2 receptors and the programming of cytokine production. Finally, IL-15Rα expressed by radiation-resistant cells is necessary and sufficient to support the survival as well as the examined maturation events of thymic iNKT cells.