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A conserved human T cell population targets mycobacterial antigens presented by CD1b

Nature Immunology volume 14, pages 706–713 (2013)Cite this article

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Abstract

Human T cell antigen receptors (TCRs) pair in millions of combinations to create complex and unique T cell repertoires for each person. Through the use of tetramers to analyze TCRs reactive to the antigen-presenting molecule CD1b, we detected T cells with highly stereotyped TCR α-chains present among genetically unrelated patients with tuberculosis. The germline-encoded, mycolyl lipid–reactive (GEM) TCRs had an α-chain bearing the variable (V) region TRAV1-2 rearranged to the joining (J) region TRAJ9 with few nontemplated (N)-region additions. Analysis of TCRs by high-throughput sequencing, binding and crystallography showed linkage of TCRα sequence motifs to high-affinity recognition of antigen. Thus, the CD1-reactive TCR repertoire is composed of at least two compartments: high-affinity GEM TCRs, and more-diverse TCRs with low affinity for CD1b-lipid complexes. We found high interdonor conservation of TCRs that probably resulted from selection by a nonpolymorphic antigen-presenting molecule and an immunodominant antigen.

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Figure 1: CD1b-restricted T cell clones generated by conventional methods.
Figure 2: Tetramer-based approaches efficiently generate CD1b-restricted T cell clones.
Figure 3: Conserved TCRs and CD4 define GEM T cells.
Figure 4: GEM TCR affinity.
Figure 5: Antigen specificity of TCR transfectants.
Figure 6: GEM TCR structures.
Figure 7: GEM T cells in polyclonal populations ex vivo.

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Acknowledgements

We thank the Tetramer Core Facility of the US National Institutes of Health for CD1b protein; M. Turner, C. Seshadri and the Shattuck Hospital for clinical collaboration; L. Tan for technical help; and the beamline staff at the Australian synchrotron for assistance with data collection. Supported by the US National Institute of Allergy and Infectious Diseases (AI04393, AR048632 to D.B.M., and K08 AI089858 to A.K.) the Burroughs Wellcome Fund, Nederlands Wetenschappelijk Onderzoek (Meervoud 836.08.001 to I.V.R.), the National Health and Medical Research Council (D.I.G. and J.R.) and the Australian Research Council (S.G.).

Author information

Authors and Affiliations

  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Ildiko Van Rhijn, Anne Kasmar, Annemieke de Jong & D Branch Moody

  2. Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

    Ildiko Van Rhijn

  3. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia

    Stephanie Gras, Mugdha Bhati & Jamie Rossjohn

  4. Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, The Netherlands

    Marieke E Doorenspleet & Niek de Vries

  5. Department of Microbiology & Immunology, University of Melbourne, Parkville, Australia

    Dale I Godfrey

  6. NIH Tetramer Core Facility, Emory Vaccine Center, Atlanta, Georgia, USA

    John D Altman

  7. Department of Pediatric Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands

    Wilco de Jager

  8. Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK

    Jamie Rossjohn

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Contributions

I.V.R. designed and did experiments and prepared the manuscript; D.B.M. supervised the experiments and prepared the manuscript; A.K. developed tetramer methods and patient cohorts and analyzed PD-1, CD161 and CD69 by flow cytometry; A.d.J. designed experiments and provided technical advice; S.G., M.B., D.I.G. and J.R. designed experiments and contributed affinity and structural data for TCRs; D.I.G., J.R. and S.G. assisted in preparation of the manuscript; W.d.J. did Luminex experiments; M.E.D. and N.d.V. did deep-sequencing experiments; and J.D.A. provided CD1b monomers.

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Correspondence to Ildiko Van Rhijn or D Branch Moody.

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Van Rhijn, I., Kasmar, A., de Jong, A. et al. A conserved human T cell population targets mycobacterial antigens presented by CD1b. Nat Immunol 14, 706–713 (2013). https://doi.org/10.1038/ni.2630

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