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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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IMMUNOBIOLOGY
Ligand-induced conformational change in the T-cell receptor associated with productive immune synapses
Ruth M. Risueño,
Diana Gil,
Edgar Fernández,
Francisco Sánchez-Madrid, and
Balbino Alarcón
From the Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, and Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain; and the Laboratory of Transplantation Immunology and Nephrology, University Hospital-Basel, Switzerland.
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 and independent of tyrosine kinase activity and that it 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 immunologic 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 on MHCp binding in vitro and in vivo, and they establish a molecular correlate for productive TCR engagement. (Blood. 2005;106:601-608)
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