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PMID: 20150895 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development.

The EMBO journal ·Vol. 29 ·No. 7 ·2010-04-07 ·Pages 1285-98

Wang H, Holst J, Woo SR, Guy C, Bettini M, Wang Y, Shafer A, Naramura M, Mingueneau M, Dragone LL, Hayes SM, Malissen B, Band H, Vignali DA

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 CD3varepsilon 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 CD3zeta-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.

MeSH Terms
Amino Acid Sequence Animals Dynamins/metabolism Gene Expression Regulation Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/chemistry,metabolism Lysine/metabolism Lysosomes/metabolism Mice Mice, Inbred C57BL Molecular Sequence Data Organ Culture Techniques Proto-Oncogene Proteins c-cbl/metabolism Receptor-CD3 Complex, Antigen, T-Cell/chemistry,genetics,metabolism T-Lymphocytes/cytology,metabolism Ubiquitination
Chemicals
Receptor-CD3 Complex, Antigen, T-Cell Proto-Oncogene Proteins c-cbl Lymphocyte Specific Protein Tyrosine Kinase p56(lck) Dynamins Lysine
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Wang Haopeng
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
Holst Jeff
Woo Seng-Ryong
Guy Cliff
Bettini Matt
Wang Yao
Shafer Aaron
Naramura Mayumi
Mingueneau Michaël
Dragone Leonard L
Hayes Sandra M
Malissen Bernard
Band Hamid
Vignali Dario A A
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2010.10
Published
2010-04-07
Epub
2010-00-11
Pages
1285-98
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2857457
Subset
IM
Grants
NCI NIH HHS · R01 CA087986 · United States
NIAID NIH HHS · AI52199 · United States
NIAID NIH HHS · R01 AI052199 · United States
NCI NIH HHS · R01 CA099163-09 · United States
NCI NIH HHS · CA087986 · United States
NIAID NIH HHS · R21 AI052199 · United States
NIAID NIH HHS · R56 AI052199 · United States
NCI NIH HHS · CA21765 · United States
NCI NIH HHS · P30 CA021765 · United States
NCI NIH HHS · CA99163 · United States
NCI NIH HHS · R01 CA099163 · United States
NCI NIH HHS · R01 CA099163-11 · United States
NCI NIH HHS · R01 CA099163-10 · United States
External Links
PubMed source DOI: 10.1038/emboj.2010.10 PMC Full Text View journal details
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