Abstract
Lipid antigens trigger help from natural killer T cells (NKT cells) for B cells, and direct conjugation of lipid agonists to antigen profoundly augments antibody responses. Here we show that in vivo, NKT cells engaged in stable and prolonged cognate interactions with B cells and induced the formation of early germinal centers. Mouse and human NKT cells formed CXCR5+PD-1hi follicular helper NKT cells (NKTFH cells), and this process required expression of the transcriptional repressor Bcl-6, signaling via the coreceptor CD28 and interaction with B cells. NKTFH cells provided direct cognate help to antigen-specific B cells that was dependent on interleukin 21 (IL-21). Unlike T cell–dependent germinal centers, those driven by NKTFH cells did not generate long-lived plasma cells. Our results demonstrate the existence of a Bcl-6-dependent subset of NKT cells specialized in providing help to B cells.
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Acknowledgements
We thank the US National Institutes of Health Tetramer Core Facility for the allophycocyanin-conjugated mouse CD1d–α-GalCer tetramer; M. Kronenberg (La Jolla Institute for Allergy and Immunology) for the baculovirus construct; P. Savage (Brigham Young University) for α-GalCer (PBS44); M. Taniguchi (RIKEN Research Center for Allergy and Immunology) for Jα18-deficient mice; M. Townsend for tissue sectioning; X. Hu, M. Srivastava and J. Ellyard for help with some experiments; and M. Pellegrini for infection of mice with L. monocytogenes. Supported by the Sylvia and Charles Viertel Charitable Foundation (C.G.V.), the European Commission (Seventh Framework Programme of the European Commission PIEF-GA-2008-220863 to P.B.), Cancer Research UK (F.D.B. and P.B.), the Royal Society (F.D.B.), the National Health and Medical Research Council of Australia (D.I.G., C.G.V., R.B., C.S.M. and S.G.T.) and the Australian Research Council (A.K.).
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P.-P.C. and P.B. designed, did and analyzed experiments and wrote the manuscript; J.F., C.S.M., A.P., A.K. and J.J.H. did experiments; V.C. and S.G.T. provided intellectual input; R.B., S.L.N. and R.B. provided reagents; D.I.G. provided reagents and intellectual input; and F.D.B. and C.G.V. contributed to the experimental design and analysis and wrote the manuscript.
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Dynamics of NKT cell help to B cells. (MOV 3520 kb)
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Chang, PP., Barral, P., Fitch, J. et al. Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat Immunol 13, 35–43 (2012). https://doi.org/10.1038/ni.2166
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DOI: https://doi.org/10.1038/ni.2166
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