Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR.
J Biol Chem
; 297(3): 101097, 2021 09.
Article
en En
| MEDLINE
| ID: mdl-34418432
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factor 3 Asociado a Receptor de TNF
/
Proteína Relacionada con TNFR Inducida por Glucocorticoide
/
Receptores Coestimuladores e Inhibidores de Linfocitos T
Límite:
Animals
Idioma:
En
Revista:
J Biol Chem
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos