Abstract
Neurofibromin 1 (NF1) is a tumor suppressor gene encoding a Ras GTPase that negatively regulates Ras signaling pathways. Mutations in NF1 are linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. In terms of antitumor immunity, CD1d-dependent natural killer T (NKT) cells play an important role in the innate antitumor immune response. Generally, Type-I NKT cells protect (and Type-II NKT cells impair) host antitumor immunity. We have previously shown that CD1d-mediated antigen presentation to NKT cells is regulated by cell signaling pathways. To study whether a haploinsufficiency in NF1 would affect CD1d-dependent activation of NKT cells, we analyzed the NKT-cell population as well as the functional expression of CD1d in Nf1+/− mice. Nf1+/− mice were found to have similar levels of NKT cells as wildtype (WT) littermates. Interestingly, however, reduced CD1d expression was observed in Nf1+/− mice compared with their WT littermates. When inoculated with a T-cell lymphoma in vivo, Nf1+/− mice survived longer than their WT littermates. Furthermore, blocking CD1d in vivo significantly enhanced antitumor activity in WT, but not in Nf1+/− mice. In contrast, a deficiency in Type-I NKT cells increased antitumor activity in Nf1+/− mice, but not in WT littermates. Therefore, these data suggest that normal NF1 expression impairs CD1d-mediated NKT-cell activation and antitumor activity against a T-cell lymphoma.
Highlights
Neurofibromatosis type 1 is an autosomal-dominant disorder caused by a mutation in a tumor suppressor gene encoding the protein neurofibromin 1 (NF1) [1], affecting 1 in 3,500 individuals worldwide
A haploinsufficiency in Neurofibromin 1 (NF1) did not seem to affect iNKT-cell development, we found that bone marrow-derived dendritic cells (BMDCs) from Nf1+/− mice expressed lower levels of CD1d on the cell surface compared with WT BMDCs (Figure 3A; Figure S1 in Supplementary Material)
Neurofibromatosis type 1 is a disease caused by mutations in the NF1 gene, a negative regulator of the Ras signaling pathway
Summary
Neurofibromatosis type 1 is an autosomal-dominant disorder caused by a mutation in a tumor suppressor gene encoding the protein neurofibromin 1 (NF1) [1], affecting 1 in 3,500 individuals worldwide. NF1 is a p21ras (Ras) guanosine triphosphatase (GTP)-activating protein (GAP). It catalyzes the hydrolysis of Ras-GTP, negatively regulating multiple Ras-dependent cellular signaling pathways [1]. Extensive studies from human tissue analyses and mouse models have discovered that loss of heterogyzosity (LOH) of NF1 in Schwann cells and a heterozygous NF1 microenvironment are both important for the formation of neurofibromas [3, 4]. LOH may explain the localized formation of tumors in patients with neurofibromatosis type 1 [1]
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