Journal Article

The Ras GTPase-Activating Protein Rasal3 Supports Survival of Naive T Cells

Muro, Ryunosuke, Ideta, Hitoshi, Nitta, Takeshi, Tsubata, Takeshi, Okada, Toshiyuki, Suzuki, Harumi

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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