Major histocompatibility complex (MHC) restricted antigen recognition: high frequency of human T-cell clones recognizing novel MHC class II determinants |
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| Authors: | E Nisbet-Brown J W Lee M Letarte J A Falk E W Gelfand |
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| Affiliation: | 1. AUDACIS, University of Antwerp, Antwerp, Belgium;2. ADREM data lab, Department of Computer Science, University of Antwerp, Antwerp, Belgium;3. Institute of Structural and Molecular Biology, University of London, London, United Kingdom;4. Department of Mathematics, Imperial College London, London, United Kingdom;5. National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel;6. Department of Industrial Engineering and Management, Ben-Gurion University of the Negev, Beer-Sheva, Israel;7. Center for Regenerative Therapies Dresden, Faculty of Medicine, TU Dresden, Dresden, Germany;8. INSERM U932, PSL University, Institut Curie, Paris 75005, France;9. Laboratoire de physique de l''Ecole normale superieure, CNRS, PSL University, Sorbonne Universite, Universite Paris-Cité, Paris 75005, France;10. Department of Physics, University of Washington, Seattle, WA, USA;11. Department of Health Technology, Technical University of Denmark, Lyngby DK-2800, Denmark;12. Sanofi R&D, Chilly-Mazarin 91380, France;13. Clinical Virology Unit, Institute of Tropical Medicine, Antwerp, Belgium;14. IBM Research Europe, Säumerstrasse 4, Rüschlikon 8803, Switzerland;15. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;p. Department of Chemical Sciences, School of Natural Sciences, University of Limerick, Limerick V94 T9PX, Ireland |
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| Abstract: | We have used antigen-specific human T-cell clones to study the relationship between MHC and antigen recognition specificities expressed by T cells. Tetanus toxoid (TT)-specific T-lymphocyte clones were derived from a immunized HLA-DR2,7 heterozygous donor by limiting dilution from peripheral blood mononuclear cells (PBM) restimulated with TT in vitro. Clones were screened for MHC-restricted antigen recognition against antigen-presenting cells (APC) from a panel of HLA-typed donors, using an in vitro T-cell proliferation assay. Several distinct patterns of antigen recognition were identified. In addition to T cells that recognized TT in association with donor class II MHC antigens, we found clones that simultaneously expressed self-restricted antigen recognition and alloreactivity, and clones with specificity for antigen in the context of MHC antigens not expressed by the T-cell donor. This was confirmed in inhibition studies using well-characterized monoclonal antibodies against class II MHC antigens to block specific proliferative responses. We propose a possible structure for the determinant recognized by two of the clones. These results suggest that the T-cell antigen receptor undergoes random or antigen-dependent changes in vitro, and that this may be a mechanism for somatic diversification of the T-cell repertoire. |
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