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Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors RORγt and Ahr that leads to IL-17 production by activated B cells

Nature Immunology volume 14, pages 514–522 (2013)Cite this article

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Abstract

Here we identified B cells as a major source of rapid, innate-like production of interleukin 17 (IL-17) in vivo in response to infection with Trypanosoma cruzi. IL-17+ B cells had a plasmablast phenotype, outnumbered cells of the TH17 subset of helper T cells and were required for an optimal response to this pathogen. With both mouse and human primary B cells, we found that exposure to parasite-derived trans-sialidase in vitro was sufficient to trigger modification of the cell-surface mucin CD45, which led to signaling dependent on the kinase Btk and production of IL-17A or IL-17F via a transcriptional program independent of the transcription factors RORγt and Ahr. Our combined data suggest that the generation of IL-17+ B cells may be a previously unappreciated feature of innate immune responses required for pathogen control or IL-17-mediated autoimmunity.

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Figure 1: B cells from T. cruzi–infected mice produce IL-17.
Figure 2: B cell production of IL-17A is required for control of infection with T. cruzi.
Figure 3: Exposure to T. cruzi trypomastigotes or purified trans-sialidase is sufficient to trigger B cell production of IL-17.
Figure 4: CD45 and Btk are required for B cell production of IL-17 in response to T. cruzi trypomastigotes or purified trans-sialidase.
Figure 5: RORγt and Ahr are not required for B cell production of IL-17 in response to T. cruzi.
Figure 6: Primary human B cells stimulated with T. cruzi produce IL-17.

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Acknowledgements

We thank K. Norris (University of Pittsburgh) for T. cruzi, Y strain; A. Weiss (University of California at San Francisco) for Cd45−/− mice; G. Sonnenberg (University of Pennsylvania) and D. Artis (University of Pennsylvania) for Il17a−/− mice; O. Campetella (Universidad de San Martín) for the trans-sialidase-neutralizing mAb (hybridoma 13G9); T. Burris (The Scripps Research Institute) for the inhibitor SR1001; N. Scharping and F. Fiocca-Vernengo for technical assistance; K. Sommer and M. Schwartz and other members of the Rawlings laboratory for suggestions and discussions; P. Abadie and MP Crespo for cell sorting; and F. Navarro for animal care in Argentina. Supported by the US National Institutes of Health (HD037091, HL075453, AI084457 and AI071163 to D.J.R.; AI 075589 to O.C.; and 5T32AR007108 and K12HD043376 to S.W.J.), the Rheumatology Research Foundation (S.W.J.), Consejo Nacional de Investigaciones Científicas y Técnicas, Agencia Nacional de Promoción Científica y Tecnológica (Fondo para la Investigación Científica y Tecnológica) and Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (A.G.) and Consejo Nacional de Investigaciones Científicas y Técnicas (D.A.B., M.C.A.-V. and M.G.-S.).

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Author notes

  1. Adriana Gruppi and David J Rawlings: These authors contributed equally to this work.

Authors and Affiliations

  1. Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina

    Daniela A Bermejo, Melisa Gorosito-Serran, Eva V Acosta-Rodriguez, Maria C Amezcua-Vesely & Adriana Gruppi

  2. Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA

    Shaun W Jackson, Blythe D Sather, Akhilesh K Singh, Socheath Khim, Mohamed Oukka & David J Rawlings

  3. Seattle Children's Research Institute, Seattle, Washington, USA

    Shaun W Jackson, Blythe D Sather, Akhilesh K Singh, Socheath Khim, Mohamed Oukka & David J Rawlings

  4. Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, San Martín, Argentina

    Juan Mucci & Oscar Campetella

  5. Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington, USA

    Denny Liggitt

  6. Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA

    Mohamed Oukka & David J Rawlings

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Contributions

D.A.B. did experiments and analyzed the results; S.W.J. did experiments, including cell-transfer studies, immunohistochemistry and additional analyses; M.G.-S. assisted with trypomastigote cultures and studies of T. cruzi–infected μMT mice; M.C.A.-V. did quantitative PCR studies and analysis; B.D.S. established and assisted with human tonsillar assays; A.K.S. did quantitative PCR studies and IL-17-related assays; S.K. assisted with mouse-colony management and cell-transfer experiments; D.L. did and interpreted tissue histopathology studies; J.M. and O.C. provided trans-sialidase and anti-trans-sialidase, and technical and intellectual contributions to assays of sialylation and desialylation; E.V.A.-R. and M.O. contributed to study design and analysis; A.G. and D.J.R. conceived of, designed and supervised the study; S.W.J., E.V.A.-R., A.G. and D.J.R. wrote the manuscript; and all authors reviewed the manuscript before submission.

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Correspondence to Adriana Gruppi or David J Rawlings.

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Bermejo, D., Jackson, S., Gorosito-Serran, M. et al. Trypanosoma cruzi trans-sialidase initiates a program independent of the transcription factors RORγt and Ahr that leads to IL-17 production by activated B cells. Nat Immunol 14, 514–522 (2013). https://doi.org/10.1038/ni.2569

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