αv Integrins regulate germinal center B cell responses through noncanonical autophagy
Fiona Raso, … , Adam Lacy-Hulbert, Mridu Acharya
Fiona Raso, … , Adam Lacy-Hulbert, Mridu Acharya
Published July 12, 2018
Citation Information: J Clin Invest. 2018;128(9):4163-4178. https://doi.org/10.1172/JCI99597.
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αv Integrins regulate germinal center B cell responses through noncanonical autophagy

Abstract

Germinal centers (GCs) are major sites of clonal B cell expansion and generation of long-lived, high-affinity antibody responses to pathogens. Signaling through TLRs on B cells promotes many aspects of GC B cell responses, including affinity maturation, class switching, and differentiation into long-lived memory and plasma cells. A major challenge for effective vaccination is identifying strategies to specifically promote GC B cell responses. Here, we have identified a mechanism of regulation of GC B cell TLR signaling, mediated by αv integrins and noncanonical autophagy. Using B cell–specific αv-KO mice, we show that loss of αv-mediated TLR regulation increased GC B cell expansion, somatic hypermutation, class switching, and generation of long-lived plasma cells after immunization with virus-like particles (VLPs) or antigens associated with TLR ligand adjuvants. Furthermore, targeting αv-mediated regulation increased the magnitude and breadth of antibody responses to influenza virus vaccination. These data therefore identify a mechanism of regulation of GC B cells that can be targeted to enhance antibody responses to vaccination.

Authors

Fiona Raso, Sara Sagadiev, Samuel Du, Emily Gage, Tanvi Arkatkar, Genita Metzler, Lynda M. Stuart, Mark T. Orr, David J. Rawlings, Shaun W. Jackson, Adam Lacy-Hulbert, Mridu Acharya

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Figure 5

Rubicon-mediated noncanonical autophagy regulates B cell TLR responses.

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Rubicon-mediated noncanonical autophagy regulates B cell TLR responses. ...
(A) MZ B cells from Rubicon-KO and control mice were stimulated in vitro with CpG DNA for the indicated times (minutes). Western blots show LC3b and actin in whole-cell lysates. Histogram shows quantification of LC3-II normalized to actin for this blot. Similar results were seen in 3 independent experiments. (B–D) Proliferation of peritoneal B1 B cells (B), sorted spleen MZ B cells (C), and spleen follicular (FO) B cells (D) from Rubicon-KO and control mice after stimulation with TLR ligands (CpG DNA, R848, and imiquimod) or anti-IgM. Proliferation was measured by [3H]-thymidine incorporation and is expressed as mean ± SD for 3 independent cultures. P values of less than 0.05 are shown (2-tailed Student’s t test). *P < 0.05; **P < 0.01. Similar results were seen in 3 independent experiments. (E) Mixed BM chimeras between control C57BL/6.SJL congenic mice and Rubicon-KO mice (CD45.2) were generated and used to assess competitive recruitment to the GC compartment as described in Figure 3. Pie charts show relative proportions of CD45.2+ cells (solid regions) in indicated B cell compartments; each pie chart represents 1 mouse. Lower panel shows data from individual mice expressed as the ratio of CD45.2/CD45.1. Also shown are the geometric means ± SD. Ratios of CD45.2/CD45.1 cells for VLP+ non-GC and GC B cells were compared by 2-tailed Student’s t test of log-transformed data. P value is shown. Similar results were seen in 2 independent experiments.