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

Abstract

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) (/) (lox) CD4-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.

Roles of WNT, NOTCH, and Hedgehog signaling in the differentiation and function of innate and innate-like lymphocytes

“…The same study showed that NOTCH signaling was not essential for differentiation of CD24 + CD44 lo (stage 0) to CD24 lo CD44 + (stage 2/3) cells [156]. Conversely, mice with a conditional knockout of NOTCH1/NOTCH2 in CD4 + cells showed an impaired maturation of NKT cells from stage 2 NK1.1 2 CD44 + cells to stage 3 NK1.1 + CD44 + cells, indicating a requirement for NOTCH signaling in late NKT cell differentiation [157]. NKT cells in the spleen express NOTCH2 on the cell surface, and NKT cells in the liver express NOTCH1 and NOTCH2, indicating that mature/ peripheral NKT cells respond to intrinsic NOTCH signaling [157,158].…”

“…Conversely, mice with a conditional knockout of NOTCH1/NOTCH2 in CD4 + cells showed an impaired maturation of NKT cells from stage 2 NK1.1 2 CD44 + cells to stage 3 NK1.1 + CD44 + cells, indicating a requirement for NOTCH signaling in late NKT cell differentiation [157]. NKT cells in the spleen express NOTCH2 on the cell surface, and NKT cells in the liver express NOTCH1 and NOTCH2, indicating that mature/ peripheral NKT cells respond to intrinsic NOTCH signaling [157,158]. Studies performed in vivo showed that NKT cells in the thymus and lymph nodes of mice with conditional knockout of NOTCH1/NOTCH2 in CD4 + cells displayed increased IL-17 expression upon a-GalCer challenge [157].…”

“…NKT cells in the spleen express NOTCH2 on the cell surface, and NKT cells in the liver express NOTCH1 and NOTCH2, indicating that mature/ peripheral NKT cells respond to intrinsic NOTCH signaling [157,158]. Studies performed in vivo showed that NKT cells in the thymus and lymph nodes of mice with conditional knockout of NOTCH1/NOTCH2 in CD4 + cells displayed increased IL-17 expression upon a-GalCer challenge [157]. Moreover, NKT cells from the liver of NOTCH1/NOTCH2 conditional knockout mice produced less IL-4 and IFN-g in vitro after stimulation with Abs against CD3 and CD28 [157].…”

Notch1 maintains dormancy of olfactory horizontal basal cells, a reserve neural stem cell

“…Additionally, Notch1 and Notch2 play different roles in diabetic nephropathy (64). Nonetheless, the interaction between the two receptors can be synergistic: for example, in gut (65) and in immune cells (66). Thus, tissue context looks to be determining their individual roles.…”

Development of invariant natural killer T cells

“…Specific deletion of Notch 1 and Notch 2 in T cells affected the development of iNKT cells [62]. Several iNKT cell populations seemed affected, as increased numbers of stage 2 and 3 iNKT cells, increased proportion of iNKT17 and altered expression of PLZF in stage 1 iNKT cells was observed.…”