Journal article
TRAF3 in T Cells Restrains Negative Regulators of LAT to Promote TCR/CD28 Signaling
The Journal of immunology (1950), Vol.207(1), pp.322-332
07/01/2021
DOI: 10.4049/jimmunol.2001220
PMCID: PMC8683566
PMID: 34145060
Abstract
The adaptor protein TNFR-associated factor 3 (TRAF3) is required for in vivo T cell effector functions and for normal TCR/CD28 signaling. TRAF3-mediated enhancement of TCR function requires engagement of both CD3 and CD28, but the molecular mechanisms underlying how TRAF3 interacts with and impacts TCR/CD28-mediated complexes to enhance their signaling remains an important knowledge gap. We investigated how TRAF3 is recruited to, and regulates, CD28 as a TCR costimulator. Direct association with known signaling motifs in CD28 was dispensable for TRAF3 recruitment; rather, TRAF3 associated with the CD28-interacting protein linker of activated T cells (LAT) in human and mouse T cells. TRAF3-LAT association required the TRAF3 TRAF-C domain and a newly identified TRAF2/3 binding motif in LAT. TRAF3 inhibited function of the LAT-associated negative regulatory protein Dok1, which is phosphorylated at an inhibitory tyrosine residue by the tyrosine kinase breast tumor kinase (Brk/PTK6). TRAF3 regulated Brk activation in T cells, limiting the association of protein tyrosine phosphatase 1B (PTP1B) with the LAT complex. In TRAF3-deficient cells, LAT complex-associated PTP1B was associated with dephosphorylation of Brk at an activating tyrosine residue, potentially reducing its ability to inhibit Dok1. Consistent with these fmdings, inhibiting PTP1B activity in TRAF3-deficient T cells rescued basal and TCR/CD28-mediated activation of Src family kinases. These results reveal a new mechanism for promotion of TCR/CD28-mediated signaling through restraint of negative regulation of LAT by TRAF3, enhancing the understanding of regulation of the TCR complex.
Details
- Title: Subtitle
- TRAF3 in T Cells Restrains Negative Regulators of LAT to Promote TCR/CD28 Signaling
- Creators
- Tina Arkee - University of IowaBruce S. Hostager - University of IowaJon C. D. Houtman - University of IowaGail A. Bishop - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.207(1), pp.322-332
- DOI
- 10.4049/jimmunol.2001220
- PMID
- 34145060
- PMCID
- PMC8683566
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Publisher
- Amer Assoc Immunologists
- Number of pages
- 12
- Grant note
- R01 AI123107; T32 AI007485; T32 GM007337 / National Institutes of Health Office of Extramural Research P30CA086862 / Holden Comprehensive Cancer Center at The University of Iowa and its National Cancer Institute Award
- Language
- English
- Date published
- 07/01/2021
- Academic Unit
- Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984297319502771
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