The Ras GTPase-activating protein neurofibromin 1 promotes the positive selection of thymocytes

Abstract

TCR-mediated activation of the Ras signaling pathway is critical for T cell development in the thymus and function in the periphery. However, which members of a family of Ras GTPase-activating proteins (RasGAPs) negatively-regulate Ras activation in T cells is unknown. In this study we examined a potential function for the neurofibromin 1 (NF1) RasGAP in the T cell lineage with the use of T cell-specific NF1-deficient mice. Surprisingly, on an MHC class I-restricted TCR transgenic background, NF1 was found to promote thymocyte positive selection. By contrast, NF1 neither promoted nor inhibited the negative selection of thymocytes. In the periphery, NF1 was found to be necessary for the maintenance of normal numbers of naïve CD4+ and CD8+ T cells but was dispensable as a regulator of TCR-induced Ras activation, cytokine synthesis, proliferation and differentiation and death. These findings point to a novel unexpected role for NF1 in T cell development as well as a regulator of T cell homeostasis.

Immune markers in the RASopathy neurofibromatosis type 1

“…However, the frequency of lymphocytes and monocytes expressing pro-inflammatory and Th1 cytokines was decreased in NF1 patients compared with controls, whereas the frequency of T lymphocytes expressing anti-inflammatory and Th2 cytokines was increased. In contrast to our results, another study showed that the secretion of cytokines appeared unchanged in T cells of NF1-deficient mice (Oliver et al, 2013). The main Th2 cytokine, IL-4, is an important cytokine for the initiation and effectiveness of Th2 immune reactions, such as allergic immune processes and tissue remodeling (Wang and Joyce, 2010).…”

“…We observed that the frequency of CD4 + (but not CD8 +) T cells was decreased in NF1 patients compared to controls. In a recent study by Oliver et al (2013), numbers of naïve CD4 + and CD8 + T cells were shown to be peripherally decreased in T cell-specific NF1-deficient mice but NF1 was dispensable as a regulator of TCR-induced Ras activation and cell proliferation. Despite our work did not evaluate the naïve phenotype or the influence of NF1 as a regulator of cell proliferation and activation results showed that the frequency of CD4 + T cells was decreased in NF1 patients compared to controls.…”

Cutting Edge: Codeletion of the Ras GTPase-Activating Proteins (RasGAPs) Neurofibromin 1 and p120 RasGAP in T Cells Results in the Development of T Cell Acute Lymphoblastic Leukemia

“…Non-conditional gene knockout mice lacking expression of either RASA1 or NF1 die in mid-gestation as a result of abnormal cardiovascular development (8–10). Therefore, to investigate the roles of RASA1 and NF1 in the T cell compartment, we had previously generated T cell-specific NF1 and RASA1-deficient mice (11, 12). RASA1 and NF1 were found to be largely dispensable for normal T cell development in non-TCR transgenic mice, although subtle alterations in the efficiency of thymocyte positive selection were apparent on TCR transgenic backgrounds.…”

The role of the immune system in neurofibromatosis type 1-associated nervous system tumors

“…In culture, both Nf1 −/− and Nf1 −/+ thymocytes as well as mature splenic T cells proliferate less after IL-2 and CD3 stimulation than wildtype [84,86], whereas unstimulated proliferation of Nf1 −/+ thymo cytes is increased compared with wild-type. Loss of Nf1 in maturing T cells leads to inhibition of positive selection in the context of MHC class I restricted T-cell receptor transgenic mice and fewer naive T cells in the spleen [85]. These data suggest that the effect of Nf1 mutation on T cells is very specific to different stages of T-cell maturation and stimulation, and may depend on Nf1 mutation in other cells of the immune compartment.…”

“…Bone marrow transplant of Nf1 null cells into immune compromised mice results in increased thymic cellularity. Targeted loss of Nf1 in maturing T cells did not lead to increased thymic cellularity, so this effect may be due to interactions between different cell types in the thymus [85]. In culture, both Nf1 −/− and Nf1 −/+ thymocytes as well as mature splenic T cells proliferate less after IL-2 and CD3 stimulation than wildtype [84,86], whereas unstimulated proliferation of Nf1 −/+ thymo cytes is increased compared with wild-type.…”