Notch 1 and Notch 2 synergistically regulate the differentiation and function of invariant NKT cells

Invariant natural killer T cells are a distinct subset of T cells that exert Janus-like functions. Moreover, Notch signaling is known to have critical roles in the development and functions of T cells. However, it is not known whether Notch signaling contributes to the development or functions of invariant natural killer T cells. Here, we found that CD4-specific gene ablation of Notch 1 and Notch 2 (N1N2^−/−) increased the number of invariant natural killer T cells in the thymus but decreased them in the liver. N1N2^−/− mice showed impaired thymic maturation of invariant natural killer T cells from the NK1.1⁻CD44⁺ to the NK1.1⁺CD44⁺ stage, resulting in accumulation of NK1.1⁻CD44⁺ invariant natural killer T cells in the thymus. Upon activation, hepatic invariant natural killer T cells from N1N2^−/− mice produced lower cytokine levels and increased apoptosis versus wild-type invariant natural killer T cells. Furthermore, Notch 1/Notch 2-deficient, but not wild type, invariant natural killer T cells failed to promote antibody-induced arthritis in CD1d^−/− mice. Unlike N1N2^−/− mice, RBP-j^lox/loxCD4-Cre mice showed similar percentages and numbers of thymic invariant natural killer T cells to wild-type mice but had defects in their homeostasis, maturation, and cytokine production in the liver. Taken together, our data indicate distinct effects of Notch signaling on invariant natural killer T cells in the thymus and liver, which are at least partly independent of RBP-j in the thymus.