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Cell. 2018 Jan 25;172(3):517-533.e20. doi: 10.1016/j.cell.2017.11.036. Epub 2017 Dec 14.

Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells.

Author information

1
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; The Francis Crick Institute, London NW1A 1AT, UK. Electronic address: contact@maurogaya.com.
2
The Francis Crick Institute, London NW1A 1AT, UK; The Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK.
3
The Francis Crick Institute, London NW1A 1AT, UK.
4
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Institute for Medical Engineering & Science, MIT, Cambridge, MA 02139, USA; Broad Institute, Cambridge, MA 02142, USA.
5
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
6
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
7
Case Western Reserve University, Cleveland, OH 44106, USA.
8
Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
9
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
10
Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, UK.
11
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; The Francis Crick Institute, London NW1A 1AT, UK; Department of Microbiology and Immunobiology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA. Electronic address: fbatista1@mgh.harvard.edu.

Abstract

B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4-producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity.

KEYWORDS:

B cells; CXCR3; IL-4; NKT cells; Zika virus; germinal center seeding; influenza; lymph node; macrophages; viral infection

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