The Ras GTPase-activating protein Rasal3 supports survival of naive T cells

• Published in: PloS one 2015-03, Vol.10 (3), p.e0119898-e0119898
• Main Authors: Muro, Ryunosuke, Nitta, Takeshi, Okada, Toshiyuki, Ideta, Hitoshi, Tsubata, Takeshi, Suzuki, Harumi
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antigens; Apoptosis; Apoptosis - genetics; B cells; CD4 antigen; CD8 antigen; Cell Differentiation - genetics; Cell Line; Cell lineage; Cell Survival; Clonal selection; Cytokines; Extracellular signal-regulated kinase; Gene Expression; Genes; GTPase-activating protein; Guanosine triphosphatases; Immunological memory; Immunology; Interleukin 7; Kinases; Lymphocytes; Lymphocytes T; MAP kinase; Medical research; Medicine; Mice; Mice, Knockout; Mice, Transgenic; Modulators; Negative selection; Pathology; Peptides; Phosphorylation; Positive selection; Protein kinase; Protein Transport; Proteins; ras GTPase-Activating Proteins - genetics; ras GTPase-Activating Proteins - metabolism; Ras protein; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Survival; T cell receptors; T cells; T-cell receptor; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Thymus; Transgenic animals
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0119898

The Ras-mitogen-activated protein kinase (MAPK) pathway is crucial for T cell receptor (TCR) signaling in the development and function of T cells. The significance of various modulators of the Ras-MAPK pathway in T cells, however, remains to be fully understood. Ras-activating protein-like 3 (Rasal3) is an uncharacterized member of the SynGAP family that contains a conserved Ras GTPase-activating protein (GAP) domain, and is predominantly expressed in the T cell lineage. In the current study, we investigated the function and physiological roles of Rasal3. Our results showed that Rasal3 possesses RasGAP activity, but not Rap1GAP activity, and represses TCR-stimulated ERK phosphorylation in a T cell line. In systemic Rasal3-deficient mice, T cell development in the thymus including positive selection, negative selection, and β-selection was unaffected. However, the number of naive, but not effector memory CD4 and CD8 T cell in the periphery was significantly reduced in Rasal3-deficient mice, and associated with a marked increase in apoptosis of these cells. Indeed, survival of Rasal3 deficient naive CD4 T cells in vivo by adoptive transfer was significantly impaired, whereas IL-7-dependent survival of naive CD4 T cells in vitro was unaltered. Collectively, Rasal3 is required for in vivo survival of peripheral naive T cells, contributing to the maintenance of optimal T cell numbers.