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

Mauro Gaya,Patricia Barral,Marianne Burbage,Shweta Aggarwal,Beatriz Montaner,Andrew Warren Navia,Malika Aid,Carlson Tsui,Paula Maldonado,Usha Nair,Khader Ghneim,Padraic G Fallon,Rafick-Pierre Sekaly,Dan H Barouch,Alex K Shalek,Andreas Bruckbauer,Jessica Strid,Facundo D Batista

doi:10.1016/j.cell.2017.11.036

Abstract

SummaryB 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.

Highlights

B cells are key elements of the adaptive immune response because they provide protection from pathogenic threats through the production of highly specific antibodies
The formation of germinal center cells was significantly reduced in NKT cell-deficient mice at early time points, whereas the expansion TfH cells remained similar throughout the infection process (Figures 1A and 1B; Figures S1A–S1D)
In NKT cell-deficient animals, germinal center structures were reduced by day 9 of infection, a defect that was accompanied by a strong decrease in the generation of influenza-specific IgG1 antibody-secreting cells (ASCs) (Figures 1C–1E)

Summary

Introduction

B cells are key elements of the adaptive immune response because they provide protection from pathogenic threats through the production of highly specific antibodies. B cells process and present pathogen-derived peptides via major histocompatibility complex (MHC) class II molecules (Amigorena et al, 1994) This results in the recruitment of specific CD4+ T cells, which help the B cells to differentiate into either antibody-secreting plasma cells or germinal center (GC) cells. B cells undergo class-switch recombination and cycles of proliferation, somatic hypermutation, and affinity-based selection, resulting in the production of high-affinity antibodies (Victora and Nussenzweig, 2012) These processes are strictly dependent on co-stimulatory signals, mainly CD40-L, ICOS, and cytokines, such as interferon g (IFN-g), interleukin-4 (IL-4), and IL-21, provided by follicular helper T (TfH) cells (Weinstein et al, 2016). Because TfH cells are known to appear later during the immune response, how B cells initially seed germinal center reactions is still unclear

Results

Discussion

Conclusion