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 3

Toso deficiency results in increased numbers of IL-10–producing B cells.

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Toso deficiency results in increased numbers of IL-10–producing B cells....
(A–C) Purified B cells from WT and Toso–/– (KO) mice were treated with BAFF, LPS, αCD40, or αIgM for 24 hours. For the last 5 hours, cells were stimulated with PMA/ionomycin in the presence of brefeldin A (BFA)/monensin and subsequently analyzed for IL-10 production. (A) Representative flow cytometric analysis. (B and C) Bar graphs show frequency (B) and absolute numbers (C) of IL-10–positive B cells. Data are mean ± SEM from 2 cultures derived from different mice. (D and E) B cells from mice with straight and conditional Toso knockout, as well as the indicated control mice, were stimulated for 5 hours with LPS and PMA/ionomycin in the presence of BFA/monensin. Frequency (D) and number (E) of IL-10–positive B cells were determined by intracellular cytokine staining. (F and G) WT and Toso–/– (KO) mice were infected i.n. with 50 PFU influenza virus strain A/PR8 (H1N1). At the indicated days p.i., splenocytes were restimulated ex vivo, and the frequency (F) and number (G) of IL-10–positive CD19+ B cells were quantified by intracellular cytokine staining. (H) CD19-Cre+/– mice and Tosof/f/CD19-Cre+/– mice were infected i.n. with 1,000 PFU influenza virus strain A/PR8 (H1N1). Lung cells isolated on day 9 p.i. were restimulated ex vivo, and number and frequency of IL-10–positive CD19+ B cells were quantified by intracellular cytokine staining. Each symbol represents an individual mouse; horizontal lines indicate the mean ± SEM. (D and E) n = 3–7; (F–H) n = 4–5. *P < 0.05; **P < 0.01; ***P < 0.001; Student’s t test. Data are representative of at least 3 independent experiments.