Journal of Experimental Medicine, Vol 183, 349-358, Copyright © 1996 by Rockefeller University Press

ARTICLES

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

S Quaratino, M Feldmann, CM Dayan, O Acuto and M Londei
Mathilda & Terence Kennedy Institute of Rheumatology, Sunley Division, London, United Kingdom.

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.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Quaratino, S., Ruf, J., Osman, M., Guo, J., McLachlan, S., Rapoport, B., Londei, M. (2005). Human Autoantibodies Modulate the T Cell Epitope Repertoire but Fail to Unmask a Pathogenic Cryptic Epitope. J. Immunol. 174: 557-563 [Abstract] [Full Text]  
• Muntasell, A., Carrascal, M., Alvarez, I., Serradell, L., van Veelen, P., Verreck, F. A. W., Koning, F., Abian, J., Jaraquemada, D. (2004). Dissection of the HLA-DR4 Peptide Repertoire in Endocrine Epithelial Cells: Strong Influence of Invariant Chain and HLA-DM Expression on the Nature of Ligands. J. Immunol. 173: 1085-1093 [Abstract] [Full Text]  
• Buzas, E. I., Hanyecz, A., Murad, Y., Hudecz, F., Rajnavolgyi, E., Mikecz, K., Glant, T. T. (2003). Differential Recognition of Altered Peptide Ligands Distinguishes Two Functionally Discordant (Arthritogenic and Nonarthritogenic) Autoreactive T Cell Hybridoma Clones. J. Immunol. 171: 3025-3033 [Abstract] [Full Text]  
• Muntasell, A., Carrascal, M., Serradell, L., Veelen, P. v., Verreck, F., Koning, F., Raposo, G., Abian, J., Jaraquemada, D. (2002). HLA-DR4 Molecules in Neuroendocrine Epithelial Cells Associate to a Heterogeneous Repertoire of Cytoplasmic and Surface Self Peptides. J. Immunol. 169: 5052-5060 [Abstract] [Full Text]  
• Vollmer, J., Weltzien, H. U., Moulon, C. (1999). TCR Reactivity in Human Nickel Allergy Indicates Contacts with Complementarity-Determining Region 3 but Excludes Superantigen-Like Recognition. J. Immunol. 163: 2723-2731 [Abstract] [Full Text]  
• Catalfamo, M., Serradell, L., Roura-Mir, C., Kolkowski, E., Sospedra, M., Vives-Pi, M., Vargas-Nieto, F., Pujol-Borrell, R., Jaraquemada, D. (1999). HLA-DM and invariant chain are expressed by thyroid follicular cells, enabling the expression of compact DR molecules. Int Immunol 11: 269-277 [Abstract] [Full Text]  
• Aichinger, G., Karlsson, L., Jackson, M. R., Vestberg, M., Vaughan, J. H., Teyton, L., Lechler, R. I., Peterson, P. A. (1997). Major Histocompatibility Complex Class II-dependent Unfolding, Transport, and Degradation of Endogenous Proteins. J. Biol. Chem. 272: 29127-29136 [Abstract] [Full Text]  
• Quaratino, S., Duddy, L. P., Londei, M. (2000). Fully competent dendritic cells as inducers of T cell anergy in autoimmunity. Proc. Natl. Acad. Sci. USA 97: 10911-10916 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS