The Journal of Experimental Medicine
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Published 6 December 2004. doi:10.1084/jem.20041251
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 11, 1455-1466
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T Cell Cross-Reactivity and Conformational Changes during TCR Engagement

Jean K. Lee1,4, Guillaume Stewart-Jones2, Tao Dong1, Karl Harlos2, Kati Di Gleria1, Lucy Dorrell1, Daniel C. Douek4, P. Anton van der Merwe3, E. Yvonne Jones2, and Andrew J. McMichael1

1 Human Immunology Unit, Medical Research Council, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, England, UK
2 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, England, UK
3 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK
4 Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Andrew J. McMichael, Human Immunology Unit, Medical Research Council, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, England, UK. Phone: 44-1865-222336; Fax: 44-1865-222600; email: andrew.mcmichael{at}ndm.ox.ac.uk

All thymically selected T cells are inherently cross-reactive, yet many data indicate a fine specificity in antigen recognition, which enables virus escape from immune control by mutation in infections such as the human immunodeficiency virus (HIV). To address this paradox, we analyzed the fine specificity of T cells recognizing a human histocompatibility leukocyte antigen (HLA)-A2–restricted, strongly immunodominant, HIV gag epitope (SLFNTVATL). The majority of 171 variant peptides tested bound HLA-A2, but only one third were recognized. Surprisingly, one recognized variant (SLYNTVATL) showed marked differences in structure when bound to HLA-A2. T cell receptor (TCR) recognition of variants of these two peptides implied that they adopted the same conformation in the TCR–peptide–major histocompatibility complex (MHC) complex. However, the on-rate kinetics of TCR binding were identical, implying that conformational changes at the TCR–peptide–MHC binding interface occur after an initial permissive antigen contact. These findings have implications for the rational design of vaccines targeting viruses with unstable genomes.

Key Words: HIV • CTL • HLA-A2 • binding conformation • fine specificity

Abbreviations used in this paper: pMHC, peptide-MHC; SFU, spot-forming units.


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