CD1d expression and NKT cells in a haploinsufficiency model of NF1 (121.20)

Abstract

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 (JML) and Watson syndrome. CD1d-dependent natural killer T (NKT) cells play an important role in anti-tumor immunity. We have shown that CD1d-mediated antigen presentation is regulated by cell signaling pathways. To study whether a haploinsufficiency in NF1 would affect CD1d-mediated activation of NKT cells, we analyzed the NKT cell population as well as CD1d expression levels from NF1+/- mice. Our results suggest that NF1+/- mice have similar levels of NKT cells as WT littermates. However, but interestingly, CD1d expression on BMDCs from NF1+/- mice was found to be lower than those from WT littermates. There was also a slight but statistically significant decrease in the splenic B220+CD1dhi population from NF1+/- mice. On the other hand, NF1+/- mice survived better than WT littermates when challenged with a T-cell lymphoma in vivo. NKT cells from NF1+/- mice were found to be more responsive to CD1d-mediated antigen presentation in vitro, which may partly explain the increased antitumor activity observed in NF1+/- mice. In conclusion, our data suggest that NF1 plays a role in negatively regulating CD1d-mediated activation of NKT cells, and this is translated in enhanced antitumor activity in mice with a haploinsufficiency in NF1.