Surface receptor Toso controls B cell–mediated regulation of T cell immunity
Jinbo Yu, … , Niko Föger, Kyeong-Hee Lee
Jinbo Yu, … , Niko Föger, Kyeong-Hee Lee
Published February 20, 2018
Citation Information: J Clin Invest. 2018;128(5):1820-1836. https://doi.org/10.1172/JCI97280.
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Research Article Immunology Inflammation

Surface receptor Toso controls B cell–mediated regulation of T cell immunity

Abstract

The immune system is tightly controlled by regulatory processes that allow for the elimination of invading pathogens, while limiting immunopathological damage to the host. In the present study, we found that conditional deletion of the cell surface receptor Toso on B cells unexpectedly resulted in impaired proinflammatory T cell responses, which led to impaired immune protection in an acute viral infection model and was associated with reduced immunopathological tissue damage in a chronic inflammatory context. Toso exhibited its B cell–inherent immunoregulatory function by negatively controlling the pool of IL-10–competent B1 and B2 B cells, which were characterized by a high degree of self-reactivity and were shown to mediate immunosuppressive activity on inflammatory T cell responses in vivo. Our results indicate that Toso is involved in the differentiation/maintenance of regulatory B cells by fine-tuning B cell receptor activation thresholds. Furthermore, we showed that during influenza A–induced pulmonary inflammation, the application of Toso-specific antibodies selectively induced IL-10–competent B cells at the site of inflammation and resulted in decreased proinflammatory cytokine production by lung T cells. These findings suggest that Toso may serve as a novel therapeutic target to dampen pathogenic T cell responses via the modulation of IL-10–competent regulatory B cells.

Authors

Jinbo Yu, Vu Huy Hoang Duong, Katrin Westphal, Andreas Westphal, Abdulhadi Suwandi, Guntram A. Grassl, Korbinian Brand, Andrew C. Chan, Niko Föger, Kyeong-Hee Lee

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Figure 5

Suppressive function of IL-10–producing Bregs.

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Suppressive function of IL-10–producing Bregs. (A–C) Bregs suppress infl...
(A–C) Bregs suppress inflammatory cytokine production in T cells in vitro. B cells from IL-10/GFP reporter (Vert-X) mice were treated for 16 hours with LPS, and PMA/ionomycin was added during the last 5 hours. B2/effector cells (B220hiGFP–), B2/IL-10 cells (B220hiGFP+), and B1/IL-10 cells (B220loGFP+) were then purified by FACS and were subsequently cocultured with naive CD8+ T cells (A and B) or naive CD4+ T cells (C). Cultures were stimulated with anti-CD3 for 48 hours and restimulated with PMA/ionomycin in the presence of BFA/monensin for 5 hours. Percentage of IFN-γ–producing (A) and TNF-α–producing (B and C) T cells was determined by intracellular cytokine staining. (D–H) Bregs suppress inflammatory cytokine production in T cells during antiviral immune response in vivo. (D) Experimental model. Briefly, naive CD19+B220hiCD1d– B2 B cells (gray), CD19+B220hiCD1d+ B2 B cells (blue), and CD19+B220lo B1a cells (red) were purified from Toso–/– (KO) mice by FACS and were adoptively transferred into C57BL/6J mice. Mice were infected i.n. with 1,000 PFU influenza virus strain A/PR8 (H1N1). On day 9 p.i., lung cells were isolated and analyzed for cytokine staining. (E–H) Number and frequency of TNF-α–producing (E and F) and IFN-γ–producing (G and H) CD4+ T cells (E and G) and CD8+ T cells (F and H). Mice that had not received adoptively transferred cells (no transfer; open squares) but were also infected with influenza were used as positive control; uninfected mice served as a negative control (open circles). Data are expressed as mean ± SEM; symbols represent individual mice. (A–C) n = 3; (E–H) n = 4–9. *P < 0.05; **P < 0.01; ***P < 0.001; 1-way ANOVA and Dunnett’s post hoc test. Data are representative of at least 3 independent experiments.