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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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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 |
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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 |
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