TRAF3 in T Cells Restrains Negative Regulators of LAT to Promote TCR/CD28 Signaling
Autor: | Tina Arkee, Jon C. D. Houtman, Bruce S. Hostager, Gail A. Bishop |
---|---|
Rok vydání: | 2021 |
Předmět: |
T-Lymphocytes
T cell CD3 Immunology Receptors Antigen T-Cell Mice Transgenic chemical and pharmacologic phenomena Article Mice 03 medical and health sciences 0302 clinical medicine CD28 Antigens medicine Animals Humans Immunology and Allergy Tyrosine Cells Cultured Mice Knockout TNF Receptor-Associated Factor 3 biology Chemistry T-cell receptor Signal transducing adaptor protein CD28 hemic and immune systems Cell biology Mice Inbred C57BL HEK293 Cells medicine.anatomical_structure biology.protein Phosphorylation Tyrosine kinase Signal Transduction 030215 immunology |
Zdroj: | J Immunol |
ISSN: | 1550-6606 0022-1767 |
Popis: | 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 findings, 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. |
Databáze: | OpenAIRE |
Externí odkaz: |