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Blood, 15 July 2005, Vol. 106, No. 2, pp. 601-608.
Prepublished online as a Blood First Edition Paper on March 24, 2005; DOI 10.1182/blood-2004-12-4763.
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Submitted December 16, 2004
Accepted March 16, 2005
A ligand-induced conformational change in the T cell receptor associated with productive immune synapses
Ruth M Risueno, Diana Gil, Edgar Fernandez, Francisco Sanchez-Madrid, and Balbino Alarcon*
Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas, Madrid, Spain
Laboratory of Transplantation Immunology and Nephrology, University Hospital-Basel, Basel, Switzerland
'Servicio de Inmunologia', 'Hospital de la Princesa', Universidad Autonoma de Madrid, Madrid, Spain
* Corresponding author; email: balarcon{at}cbm.uam.es.
Triggering of the T cell receptor (TCR) can produce very different responses depending on the nature of the Major Histocompatibility Complex/antigen peptide (MHCp) ligand. The molecular mechanisms that permit such fine discrimination are still unknown. We show here that an epitope in the cytoplasmic tail of the TCR CD3 subunit, recognized by antibody APA1/1, is only detected when the TCR is fully activated. Exposure of the APA1/1 epitope is shown to be fast, independent of tyrosine kinase activity and takes place even when T cells are stimulated at 0°C. These results suggest that APA1/1 detects a conformational change in the TCR. APA1/1 staining concentrates in a restricted area of the immunological synapse. Most important, we show that full agonist but not partial agonist peptides induce exposure of the APA1/1 epitope, indicating a correlation between the induction of the conformational change in the TCR and full T cell activation. Finally, the conformational change is shown to occur in T cells that are being stimulated by antigen in vivo. Therefore, these results demonstrate that the TCR undergoes a conformational change upon MHCp binding both in vitro and in vivo, and establish a molecular correlate for productive TCR engagement.
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