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

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Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells Article Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells Graphical Abstract Authors Mauro Gaya, Patricia Barral, Marianne Burbage, ..., Andreas Bruckbauer, Jessica Strid, Facundo D. Batista Correspondence [email protected] (M.G.), [email protected] (F.D.B.) In Brief NKT cells are required for the initial formation of germinal centers and production of effective neutralizing antibody responses against viruses. Highlights d NKT cells promote B cell immunity upon viral infection d NKT cells are primed by lymph-node-resident macrophages d NKT cells produce early IL-4 wave at the follicular borders d Early IL-4 wave is required for efficient seeding of germinal centers Gaya et al., 2018, Cell 172, 1–17 January 25, 2018 ª 2017 The Authors. Published by Elsevier Inc. https://doi.org/10.1016/j.cell.2017.11.036 Please cite this article in press as: Gaya et al., Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells, Cell (2018), https://doi.org/10.1016/j.cell.2017.11.036 Article Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells Mauro Gaya,1,2,* Patricia Barral,2,3 Marianne Burbage,2 Shweta Aggarwal,2 Beatriz Montaner,2 Andrew Warren Navia,1,4,5 Malika Aid,6 Carlson Tsui,2 Paula Maldonado,2 Usha Nair,1 Khader Ghneim,7 Padraic G. Fallon,8 Rafick-Pierre Sekaly,7 Dan H. Barouch,1,6 Alex K. Shalek,1,4,5 Andreas Bruckbauer,2 Jessica Strid,9 and Facundo D. Batista1,2,10,11,* 1Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA 2The Francis Crick Institute, London NW1A 1AT, UK 3The Peter Gorer Department of Immunobiology, King’s College London, London SE1 9RT, UK 4Institute for Medical Engineering & Science, MIT, Cambridge, MA 02139, USA 5Broad Institute, Cambridge, MA 02142, USA 6Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA 7Case Western Reserve University, Cleveland, OH 44106, USA 8Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland 9Division of Immunology and Inflammation, Department of Medicine, Imperial College London, London W12 0NN, UK 10Department of Microbiology and Immunobiology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA 02115, USA 11Lead Contact *Correspondence: [email protected] (M.G.), [email protected] (F.D.B.) https://doi.org/10.1016/j.cell.2017.11.036 SUMMARY through the production of highly specific antibodies. In the past few years, there has been much attention on the generation B cells constitute an essential line of defense from of broadly neutralizing antibodies against highly variable or pathogenic infections through the generation of emerging pathogens, such as influenza, HIV, and Zika virus to class-switched antibody-secreting cells (ASCs) in develop effective vaccines capable of conferring broad and germinal centers. Although this process is known to long-lasting immunity. Therefore, it is crucial to understand be regulated by follicular helper T (TfH) cells, the mech- how viruses elicit B cell immunity during an infection process. anism by which B cells initially seed germinal center Pathogen recognition occurs in secondary lymphoid organs such as the spleen and lymph nodes (Batista and Harwood, reactions remains elusive. We found that NKT cells, a 2009). In the lymph nodes, B cells recognize pathogens on the population of innate-like T lymphocytes, are critical surface of subcapsular sinus (SCS) macrophages, migratory for the induction of B cell immunity upon viral infection. dendritic cells, and follicular dendritic cells (Carrasco and Ba- The positioning of NKT cells at the interfollicular areas tista, 2007; Gaya et al., 2015; Heesters et al., 2013; Junt et al., of lymph nodes facilitates both their direct priming by 2007; Phan et al., 2007; Qi et al., 2006). Following pathogen resident macrophages and the localized delivery of recognition, B cells process and present pathogen-derived pep- innate signals to antigen-experienced B cells. Indeed, tides via major histocompatibility complex (MHC) class II mole- NKT cells secrete an early wave of IL-4 and constitute cules (Amigorena et al., 1994). This results in the recruitment of + up to 70% of the total IL-4-producing cells during the specific CD4 T cells, which help the B cells to differentiate initial stages of infection. Importantly, the requirement into either antibody-secreting plasma cells or germinal center of this innate immunity arm appears to be evolution- (GC) cells. Within germinal centers, B cells undergo class-switch recombination and cycles of proliferation, somatic hypermuta- arily conserved because early NKT and IL-4 gene tion, and affinity-based selection, finally resulting in the produc- signatures also positively correlate with the levels tion of high-affinity antibodies (Victora and Nussenzweig, 2012). of neutralizing antibodies in Zika-virus-infected ma- These processes are strictly dependent on co-stimulatory sig- caques. In conclusion, our data support a model nals, mainly CD40-L, ICOS, and cytokines, such as interferon g wherein a pre-TfH wave of IL-4 secreted by interfollic- (IFN-g), interleukin-4 (IL-4), and IL-21, provided by follicular ular NKT cells triggers the seeding of germinal center helper T (TfH) cells (Weinstein et al., 2016). Because TfH cells cells and serves as an innate link between viral infec- are known to appear later during the immune response, how tion and B cell immunity. B cells initially seed germinal center reactions is still unclear. In addition to pathogen-derived peptides, B cells are able to INTRODUCTION present glycolipid antigens, such as those present on the surface of Sphingomonas species (spp.), Borrelia burgdorferi, and Strep- B cells are key elements of the adaptive immune response tococcus pneumoniae, on CD1d molecules (Barral et al., because they provide protection from pathogenic threats 2008; Kinjo et al., 2011; Leadbetter et al., 2008). Populations of Cell 172, 1–17, January 25, 2018 ª 2017 The Authors. Published by Elsevier Inc. 1 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Gaya et al., Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells, Cell (2018), https://doi.org/10.1016/j.cell.2017.11.036 A Uninfected CD1d-/- **** 11 Uninfected 105 4 4.6% 10 0.9% 9.5% CD1d-/- B cells (%) 5.5 103 + GL7 + 0 Fas 0 Fas 010103 104 5 GL7 B Uninfected CD1d-/- 105 24 Uninfected 104 4.3% 17.9% 18.6% -/- T cells (%) T CD1d + 12 103 PD-1 + 0 0 CXCR5 010103 104 5 CXCR5 PD-1 C Uninfected CD1d-/- IgD GL7 E D ** ** * 18000 10 0.4 Uninfected Uninfected area + CD1d-/- -/- 9000 CD1d 5 0.2 area /IgD -IAV IgG1 ASC/LN IgG1 -IAV + α structures / section + GL7 0 0 0 GL7 F Uninfected Wild type/Vaccinia CD1d-/-/Vaccinia ** 18 Uninfected 105 Wild type/Vaccinia 0.3% 14.7% 7.8% 4 10 CD1d-/-/Vaccinia B cells (%) 9 103 + GL7 + 0 Fas Fas 0 010103 104 5 GL7 G Uninfected Wild type/Vaccinia CD1d-/-/Vaccinia 24 Uninfected 105 Wild type/Vaccinia 4 10 4.7% 19.8% 17.0% -/- T cells (%) T CD1d /Vaccinia + 12 103 PD-1 + 0 0 CXCR5 CXCR5 010103 104 5 PD-1 (legend on next page) 2 Cell 172, 1–17, January 25, 2018 Please cite this article in press as: Gaya et al., Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells, Cell (2018), https://doi.org/10.1016/j.cell.2017.11.036 CD1d-restricted, innate-like T cells, known as natural killer (NK)T process (Figures 1A and 1B; Figures S1A–S1D). We further cells, recognize these lipids and provide cognate help to B cells. compared the spatial organization of germinal centers in wild- This NKT cell-mediated help enhances the production of anti- type and CD1dÀ/À mice by immunohistochemistry. In wild-type bodies by B cells (Bai et al., 2013; Barral et al., 2008; Leadbetter animals, influenza infection induces both the enlargement of et al., 2008). Because there are no reports of lipid antigens orig- IgD+ B cell follicles as well as the formation of follicular GL7+ inating from viruses, it is currently unclear whether NKT cells structures corresponding to germinal centers (Figure 1C). In have a role in inducing antiviral B cell responses. contrast, in NKT cell-deficient animals, germinal center struc- Here we show that, following respiratory viral infection, NKT tures were reduced by day 9 of infection, a defect that cell-deficient mice are impaired in their ability to form germinal was accompanied by a strong decrease in the generation of centers and immunoglobulin G (IgG) class-switched antibody- influenza-specific IgG1 ASCs (Figures 1C–1E). Interestingly, secreting cells (ASCs). In a striking contrast to B cell activation CD1dÀ/À mice also displayed a significant reduction in germinal by glycolipid antigens, CD1d-mediated interactions between center formation when infected with the vaccinia virus Western B cells and NKT cells are dispensable during viral infection. Reserve strain, suggesting that the ability of NKT cells to pro- Instead, NKT cells promote B cell immunity through the early mote B cell responses is a general feature of viral infections (Fig- and localized production of IL-4 at the follicular borders, a pro- ures 1F and 1G). cess that is likely driven by CXCR3 and requires initial priming To address whether NKT cells would also induce B cell immu- by resident macrophages through CD1d and IL-18. Importantly, nity after vaccination with viral antigens, we intranasally immu- this seems to be a conserved process because transcriptomic nized wild-type and CD1dÀ/À mice with hemagglutinin (HA) analysis of Zika-virus-infected macaques shows that early NKT trimmer from the PR8 influenza strain in the presence or absence and IL-4 gene signatures positively correlate with the levels of of two different adjuvants: alpha-galactosylceramide (a-GalCer) Zika-specific neutralizing antibodies.
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