Tonic ubiquitylation controls T‐cell receptor:CD3 complex expression during T‐cell development |
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| Authors: | Yao Wang Mayumi Naramura Leonard L Dragone Sandra M Hayes Bernard Malissen Hamid Band Dario A A Vignali |
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| Affiliation: | 1. Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA;2. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA;3. Division of Pediatric Immunology, Rheumatology, and Allergy, National Jewish Health and Denver Children's Hospital, Denver, CO, USA;4. Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, USA;5. Centre d'Immunologie de Marseille‐Luminy, INSERM U631‐CNRS UMR, Université de la Méditerranée, Marseille Cedex, France;6. Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA;7. Department of Pathology, University of Tennessee Health Science Center, Memphis, TN, USA |
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| Abstract: | Expression of the T‐cell receptor (TCR):CD3 complex is tightly regulated during T‐cell development. The mechanism and physiological role of this regulation are unclear. Here, we show that the TCR:CD3 complex is constitutively ubiquitylated in immature double positive (DP) thymocytes, but not mature single positive (SP) thymocytes or splenic T cells. This steady state, tonic CD3 monoubiquitylation is mediated by the CD3ε proline‐rich sequence, Lck, c‐Cbl, and SLAP, which collectively trigger the dynamin‐dependent downmodulation, lysosomal sequestration and degradation of surface TCR:CD3 complexes. Blocking this tonic ubiquitylation by mutating all the lysines in the CD3 cytoplasmic tails significantly upregulates TCR levels on DP thymocytes. Mimicking monoubiquitylation by expression of a CD3ζ‐monoubiquitin (monoUb) fusion molecule significantly reduces TCR levels on immature thymocytes. Moreover, modulating CD3 ubiquitylation alters immunological synapse (IS) formation and Erk phosphorylation, thereby shifting the signalling threshold for positive and negative selection, and regulatory T‐cell development. Thus, tonic TCR:CD3 ubiquitylation results in precise regulation of TCR expression on immature T cells, which is required to maintain the fidelity of T‐cell development. |
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| Keywords: | c‐Cbl signalling T‐cell development T‐cell receptor:CD3 ubiquitylation |
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