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Human self-reactive T cell clones expressing identical T cell receptor beta chains differ in their ability to recognize a cryptic self-epitope.
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MedLine Citation:
PMID:  8627148     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recognition of self-antigens by T lymphocytes is a central event in autoimmunity. Understanding of the molecular interactions between T cell receptors (TCR) and self-epitopes may explain how T cells escape thymic education and initiate an autoimmune reaction. We have studied five human in vivo activated T cell clones specific for the region 535-551 of human thyroid peroxidase (TPO) established from a Graves' patient. Three clones (37, 72, and 73) expressed identical TCR beta and alpha chains rearranging V beta 1.1 and V alpha 15.1, and were considered sister clones. Clone 43 differed from clone 37 and its sisters in the J alpha region only. Clone NP-7 expressed V beta 6.5 but rearranged two in-frame TCR alpha chain, both using the V alpha 22.1 segment. Fine epitope mapping using nested peptides showed that clones using identical TCR beta chains, identical V alpha, but a different J alpha recognized distinct, nonoverlapping epitopes in the TPO 535-551 region. This finding shows that a different J alpha region alone leads to a heterogeneous pattern of recognition. This indicates that the "restricted" TCR V region usage sometimes found in autoimmune diseases may not always correspond to identical epitope recognition. To confirm that clones 37 (and its sisters) and 43 recognize different epitopes, the T cell clones were stimulated with a TPO-transfected autologous Epstein-Barr virus (EBV) cell line (TPO-EBV) that presents TPO epitopes afer endogenous processing. Only clone 37 and its sisters recognizes the TPO-EBV cell line, suggesting that the epitope recognized by clone 43 is not presented upon endogenous processing. We have shown that thyroid epithelial cells (TEC), the only cells that produce TPO, express HLA class II molecules in Graves' disease and can act as an antigen-presenting cells, presenting TPO after endogenous processing to autoantigen-reactive T cell clones. We tested, therefore, whether autologous TEC induced the same pattern of stimulation as TPO-EBV; T cell clone 37 recognizes the TEC, whereas it is stimulated poorly by the TPO loaded to autologous peripheral blood mononuclear cells (PBMC). Clone 43, which fails to recognize the TPO-EBV, also fails to recognize the TEC, but is activated by exogenous TPO presented by autologous PBMC. These results show that exogenous versus endogenous processing in vivo generates a different TPO epitope repertoire, producing a "cryptic" epitope (epitope not always available for recognition). Our findings define a route by which human self-reactive T cells may escape thymic selection and become activated in vivo, thus possibly leading to autoimmunity.
Authors:
S Quaratino; M Feldmann; C M Dayan; O Acuto; M Londei
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of experimental medicine     Volume:  183     ISSN:  0022-1007     ISO Abbreviation:  J. Exp. Med.     Publication Date:  1996 Feb 
Date Detail:
Created Date:  1996-06-27     Completed Date:  1996-06-27     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2985109R     Medline TA:  J Exp Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  349-58     Citation Subset:  IM    
Affiliation:
Mathilda & Terence Kennedy Institute of Rheumatology, Sunley Division, London, United Kingdom.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/X84687;  X89751;  X89752;  X89753;  X89754;  X89809;  X89860
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Autoantigens*
Base Sequence
Epithelium / immunology
Epitope Mapping
Epitopes*
Graves Disease / immunology*
HLA-DQ Antigens
Herpesvirus 4, Human / genetics
Humans
Iodide Peroxidase / genetics,  immunology
Lymphocyte Activation
Molecular Sequence Data
Polymerase Chain Reaction
Receptors, Antigen, T-Cell, alpha-beta*
Sequence Analysis, DNA
T-Lymphocytes / immunology*
Thyroid Gland / enzymology,  immunology
Transfection
Grant Support
ID/Acronym/Agency:
//Wellcome Trust
Chemical
Reg. No./Substance:
0/Autoantigens; 0/Epitopes; 0/HLA-DQ Antigens; 0/Receptors, Antigen, T-Cell, alpha-beta; EC 1.11.1.8/Iodide Peroxidase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): J Exp Med
ISSN: 0022-1007
ISSN: 1540-9538
Publisher: The Rockefeller University Press
Article Information
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Print publication date: Day: 1 Month: 2 Year: 1996
Volume: 183 Issue: 2
First Page: 349 Last Page: 358
ID: 2192455
Publisher Id: 96195189
PubMed Id: 8627148

Human self-reactive T cell clones expressing identical T cell receptor beta chains differ in their ability to recognize a cryptic self-epitope


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