Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
| Autor: | Tina Arkee, Hanzeng Li, Gail A. Bishop, Bruce S. Hostager |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
TRAF3
MAPK/ERK pathway Male NLS nuclear localization sequence medicine.medical_treatment T cell T-Lymphocytes receptor NKT natural killer T cell Lymphocyte Activation Biochemistry Receptors Tumor Necrosis Factor Mice Costimulatory and Inhibitory T-Cell Receptors T-cell Glucocorticoid-Induced TNFR-Related Protein TRAF medicine Animals GITR LMC littermate control Molecular Biology Mice Knockout biology TNFRSF18 TNF Receptor-Associated Factor 3 CAR-T chimeric antigen receptor T cell NF-kappa B JAK1 Janus-activated kinase 1 Cell Biology Natural killer T cell TNFR tumor necrosis factor receptor Cell biology Mice Inbred C57BL Treg T regulatory cell Cytokine medicine.anatomical_structure Mitogen-activated protein kinase biology.protein Interleukin-2 Female Signal transduction signal transduction MAPK mitogen-activated protein kinase TRAF3 TNFR-associated factor 3 Research Article adaptor protein |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Tumor necrosis factor receptor (TNFR)-associated factor 3 (TRAF3) plays context-specific roles in multiple receptor-mediated signaling pathways in different cell types. Mice lacking TRAF3 in T cells display defective T-cell-mediated immune responses to immunization and infection and demonstrate defective early signaling via the TCR complex. However, the role of TRAF3 in the function of GITR/TNFRSF18, an important costimulatory member of the TNFR superfamily, is unclear. Here we investigated the impact of T cell TRAF3 status on both GITR expression and activation of specific kinases in the GITR signaling pathway in T cells. Our results indicate that TRAF3 negatively regulates GITR functions in several ways. First, expression of GITR protein was elevated in TRAF3-deficient T cells, resulting from both transcriptional and posttranslational regulation that led to greater GITR transcript levels, as well as enhanced GITR protein stability. TRAF3 associated with T cell GITR in a manner dependent upon GITR ligation. TRAF3 also inhibited several events of the GITR mediated early signaling cascade, in a manner independent of recruitment of phosphatases, a mechanism by which TRAF3 inhibits signaling through several other cytokine receptors. These results add new information to our understanding of GITR signaling and function in T cells, which is relevant to the potential use of GITR to enhance immune therapies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|