Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences of Nf1 deficiency in T-cell development and function

• Published in: Blood 2002-11, Vol.100 (10), p.3656-3662
• Main Authors: INGRAM, David A, LEI ZHANG, MCCARTHY, Jennifer, WENNING, Mary Jo, FISHER, Lucy, YANG, Feng-Chun, CLAPP, D. Wade, KAPUR, Reuben
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunobiology; Lymphocyte Activation; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Lymphoproliferative Disorders - etiology; Lymphoproliferative Disorders - immunology; Lymphoproliferative Disorders - metabolism; Mice; Mice, Mutant Strains; Neurofibromin 1 - deficiency; Neurofibromin 1 - immunology; Neurofibromin 1 - physiology; ras Proteins - metabolism; Spleen - cytology; T-Lymphocyte Subsets; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Thymus Gland - cytology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-03-0734

Ras plays an essential role in lymphocyte development and function. However, in vivo consequence(s) of regulation of Ras activity by guanosine triphosphatase (GTPase)-activating proteins (GAPs) on lymphocyte development and function are not known. In this study we demonstrate that neurofibromin, the protein encoded by the NF1 tumor suppressor gene functions as a GAP for Ras in T cells. Loss of Nf1 in T cells results in enhanced Ras activation, which is associated with thymic and splenic hyperplasia, and an increase in the absolute number of immature and mature T-cell subsets compared with control mice. Interestingly, in spite of a profound T-cell expansion and higher thymidine incorporation in unstimulated Nf1-deficient T cells, T-cell receptor and interleukin-2 receptor-mediated proliferation of thymocytes and mature T cells was substantially reduced compared with control mice. Collectively, these results identify neurofibromin as a GAP for Ras in T cells for maintaining immune homeostasis in vivo.