Journal article
Effective functional maturation of invariant natural killer T cells is constrained by negative selection and T-cell antigen receptor affinity
R Bedel, R Berry, T Mallevaey, JL Matsuda, J Zhang, DI Godfrey, J Rossjohn, JW Kappler, P Marrack, L Gapin
Proceedings of the National Academy of Sciences of the United States of America | Published : 2014
Abstract
The self-reactivity of their T-cell antigen receptor (TCR) is thought to contribute to the development of immune regulatory cells, such as invariant NK T cells (iNKT). In the mouse, iNKT cells express TCRs composed of a unique Vα14-Jα18 rearrangement and recognize lipid antigens presented by CD1d molecules. We created mice expressing a transgenic TCR-β chain that confers high affinity for self-lipid/CD1d complexes when randomly paired with the mouse iNKT Vα14-Jα18 rearrangement to study their development. We show that although iNKT cells undergo agonist selection, their development is also shaped by negative selection in vivo. In addition, iNKT cells that avoid negative selection in these mi..
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Awarded by National Institute of Allergy and Infectious Diseases
Funding Acknowledgements
We thank members of the L. G. laboratory, John Cambier, and Leonard Dragone for thoughtful discussion and critical comments on the manuscript; Derek Sant'Angelo for the antipromyelocytic zinc finger transcription factor mAb used in preliminary experiments; the National Jewish Health flow cytometry facility, the Mucosal and Vaccine Research Colorado Flow Core, and the University of Colorado flow cytometry shared resource facility for assistance with cell sorting; the Center for Genes, Environment, and Health at National Jewish Health for sequencing and the National Institutes of Health core facility for CD1d tetramers. This work was supported by National Institutes of Health Grants AI18785 and AI22295 (to P. M. and J.W.K.), and AI092108 (to L. G.); The Cancer Center Support Grant P30CA046934; the Howard Hughes Medical Institute (P. M. and J.W. K.); the National Health and Medical Research Council (NHMRC) Australia Fellowship (to J.R.); the NHMRC Senior Principal Research Fellowship (to D. I. G.); a NHMRC Peter Doherty fellowship (to Richard Berry); NHMRC Program grants (to D. I. G.); and a Cancer Council of Victoria grant (to J.R. and D.I.G.).