Cargando…

Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR

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 defe...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Hanzeng, Hostager, Bruce S., Arkee, Tina, Bishop, Gail A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441216/
https://www.ncbi.nlm.nih.gov/pubmed/34418432
http://dx.doi.org/10.1016/j.jbc.2021.101097
_version_ 1783752830552637440
author Li, Hanzeng
Hostager, Bruce S.
Arkee, Tina
Bishop, Gail A.
author_facet Li, Hanzeng
Hostager, Bruce S.
Arkee, Tina
Bishop, Gail A.
author_sort Li, Hanzeng
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8441216
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher American Society for Biochemistry and Molecular Biology
record_format MEDLINE/PubMed
spelling pubmed-84412162021-09-20 Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR Li, Hanzeng Hostager, Bruce S. Arkee, Tina Bishop, Gail A. J Biol Chem Research Article 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. American Society for Biochemistry and Molecular Biology 2021-08-18 /pmc/articles/PMC8441216/ /pubmed/34418432 http://dx.doi.org/10.1016/j.jbc.2021.101097 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Li, Hanzeng
Hostager, Bruce S.
Arkee, Tina
Bishop, Gail A.
Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
title Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
title_full Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
title_fullStr Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
title_full_unstemmed Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
title_short Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
title_sort multiple mechanisms for traf3-mediated regulation of the t cell costimulatory receptor gitr
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441216/
https://www.ncbi.nlm.nih.gov/pubmed/34418432
http://dx.doi.org/10.1016/j.jbc.2021.101097
work_keys_str_mv AT lihanzeng multiplemechanismsfortraf3mediatedregulationofthetcellcostimulatoryreceptorgitr
AT hostagerbruces multiplemechanismsfortraf3mediatedregulationofthetcellcostimulatoryreceptorgitr
AT arkeetina multiplemechanismsfortraf3mediatedregulationofthetcellcostimulatoryreceptorgitr
AT bishopgaila multiplemechanismsfortraf3mediatedregulationofthetcellcostimulatoryreceptorgitr