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

Hanzeng Li; Bruce S. Hostager; Tina Arkee; Gail A. Bishop

doi:10.1016/j.jbc.2021.101097

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

Journal article

Open access

Peer reviewed

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

Hanzeng Li, Bruce S. Hostager, Tina Arkee and Gail A. Bishop

The Journal of biological chemistry, Vol.297(3), pp.101097-101097

09/2021

DOI: 10.1016/j.jbc.2021.101097

PMCID: PMC8441216

PMID: 34418432

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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.

adaptor protein

GITR

receptor

signal transduction

T-cell

TRAF

Details

Title: Subtitle: Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR
Creators: Hanzeng Li - University of Iowa
Bruce S. Hostager - University of Iowa
Tina Arkee - University of Iowa
Gail A. Bishop - University of Iowa
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.297(3), pp.101097-101097
DOI: 10.1016/j.jbc.2021.101097
PMID: 34418432
PMCID: PMC8441216
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000054, name: National Cancer Institute, award: P30CA086862; DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs; DOI: 10.13039/100006379, name: Office of Research and Development; DOI: 10.13039/100007217, name: Health Services Research and Development; DOI: 10.13039/100008893, name: University of Iowa; DOI: 10.13039/100000002, name: NIH, award: AI007485, R01 AI123107, GM007337
Language: English
Date published: 09/2021
Academic Unit: Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984297440302771

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