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Reciprocal regulation of polarized cytokine production by effector B and T cells

Nature Immunology volume 1, pages 475–482 (2000)Cite this article

Abstract

Although B cells produce cytokines it is not known whether B cells can differentiate into effector subsets that secrete polarized arrays of cytokines. We have identified two populations of “effector” B cells (Be1 and Be2) that produce distinct patterns of cytokines depending on the cytokine environment in which the cells were stimulated during their primary encounter with antigen and T cells. These effector B cell subsets subsequently regulate the differentiation of naïve CD4+ T cells to TH1 and TH2 cells through production of polarizing cytokines such as interleukin 4 and interferon γ. In addition, Be1 and Be2 cells could be identified in animals that were infected with pathogens that preferentially induce a Type 1 or Type 2 immune response. Together these results suggest that, in addition to their well defined role in antibody production, B cells may regulate immune responses to infectious pathogens through their production of cytokines.

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Figure 1: Differentially regulated production of cytokines by B cell subsets.
Figure 2: Distinct patterns of cytokine production by Be1 and Be2 subsets.
Figure 3: Be1 and Be2 cells induce the polarization of naïve T cells into TH1-like and TH2-like effectors.
Figure 4: IFN-γ production by Be1 cells and IL-4 production by Be2 cells are sufficient to drive polarization of naïve T cells.
Figure 5: Polarized production of cytokines by B cells following infection with T. gondii or H. polygyrus.

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Acknowledgements

We thank T. Randall and S. Smiley for discussion and their comments on the manuscript. Supported by NIH grants AI22125 (to D. P. H. and S. L. S.) and AI43629 (to F. E. L.) and by the Trudeau Institute Inc.

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  1. Trudeau Institute, Saranac Lake, 12983, NY, USA

    David P. Harris, Laura Haynes, Peter C. Sayles, Debra K. Duso, Sheri M. Eaton, Nancy M. Lepak, Lawrence L. Johnson, Susan L. Swain & Frances E. Lund

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Supplementary information

Web Figure 1.

The influence of BCR ligation on expansion and cytokine production by effector B cells. Naïve B cells from MD4 BCR transgenic mice were cultured with mytomycin c treated TH1 or TH2 effector cells, PCCF, ± HEL as indicated, for 3 or 4 days. Cells cultured for 4 days received 100 ng/ml IL-2 on d 2 to prolong B cell viability. On days 3 and d4 the B cells were collected and repurified by positive selection using magnetic columns. After repurification >99% of the cells were CD19+, B220+. The repurified B cells were then stimulated in vitro with PMA + Ca2+ ionophore and supernatants were collected after 72 h. (a) B cell recovery on d 3 and d 4 after repurification. (b-d) Cytokine production by repurified, PMA + Ca2+ ionopho-rerestimulated B cells after culturing for 4 d with TH1 (open bars) or TH2 (solid bars) effector cells ± HEL as indicated. Cytokine production was measured by ELISA. (GIF 10 kb)

Web Figure 2.

In vitro polarization of naive T cells by Be1 and Be2 cells occurs in the absence of BCR ligation. Effector Be1 and Be2 cells were generated by culturing naïve B cells from MD4 BCR transgenic mice with mytomycin C treated TH1 and TH2 effector cells and antigen (PCCF + HEL) for 3 d. The Be1 and Be2 cells were collected, repurified by positive selection and cultured with purified naïve, CD4+ T cells from AND TCR transgenic mice (1:2 ratio), and PCCF + IL-2 alone, with PCCF + IL-2 + anti-IgM or with PCCF + IL-2 + HEL. The purity of the Be1, Be2 cells and naive CD4 T cells used in this experiment was > 98%. On d 4, T cells were collected, washed and restimulated in vitro with plate-bound anti-CD3 + soluble anti-CD28. Supernatants were collected at 24 and 72 h and tested for cytokines by bioassay or cytokine-specific ELISA. The cytokines produced by T cells incubated with Be1 effectors (+ or - antigen) is shown in open bars and the cytokines produced by T cells incubated with Be2 cells (± antigen) is shown in filled bars. The data are shown as maximum cytokine detected at either 24 or 72 hours (mean±s.d. of triplicate wells). (GIF 7 kb)

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Harris, D., Haynes, L., Sayles, P. et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 1, 475–482 (2000). https://doi.org/10.1038/82717

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