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Suppression by TFR cells leads to durable and selective inhibition of B cell effector function

Nature Immunology volume 17, pages 14361446 (2016) | Download Citation

Abstract

Follicular regulatory T cells (TFR cells) inhibit follicular helper T cell (TFH cell)–mediated antibody production. The mechanisms by which TFR cells exert their key immunoregulatory functions are largely unknown. Here we found that TFR cells induced a distinct suppressive state in TFH cells and B cells, in which effector transcriptional signatures were maintained but key effector molecules and metabolic pathways were suppressed. The suppression of B cell antibody production and metabolism by TFR cells was durable and persisted even in the absence of TFR cells. This durable suppression was due in part to epigenetic changes. The cytokine IL-21 was able to overcome TFR cell–mediated suppression and inhibited TFR cells and stimulated B cells. By determining mechanisms of TFR cell-mediated suppression, we have identified methods for modulating the function of TFR cells and antibody production.

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Acknowledgements

We thank the Nikon Imaging Center at Harvard Medical School for help with light microscopy and the MBIB flow cytometry core for help with flow cytometry. Supported by the US National Institute of Health (T32HL007627 to P.T.S.; and R37AI38310, P01AI56299 and P01AI065687 to A.H.S.) and the Evergrande Center for Immunologic Diseases.

Author information

Affiliations

  1. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Peter T Sage
    • , Vikram R Juneja
    • , Seth Maleri
    •  & Arlene H Sharpe
  2. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Peter T Sage
    • , Vikram R Juneja
    • , Seth Maleri
    • , Waradon Sungnak
    • , Vijay K Kuchroo
    •  & Arlene H Sharpe
  3. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.

    • Noga Ron-Harel
    •  & Marcia Haigis
  4. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Debattama R Sen
    •  & W Nicholas Haining
  5. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Waradon Sungnak
    •  & Vijay K Kuchroo
  6. FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.

    • Nicolas Chevrier
  7. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Arlene H Sharpe

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Contributions

P.T.S. performed all experiments and analyzed data; N.R.-H. performed metabolic-flux analysis; N.R.-H. and M.H. provided technical help on metabolic pathways; V.R.J. provided technical help on RNA-seq experiments; D.R.S. and W.N.H. prepared ATAC-seq samples and provided technical assistance on ATAC-seq analysis; S.M. provided technical help; W.S. and V.K.K. provided Il21r−/− mice and technical help; N.C. provided the RNA-seq library-preparation protocol and provided technical help; and P.T.S. and A.H.S. conceived of the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Arlene H Sharpe.

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    Supplementary Video 1

    Time lapse movie showing TFR cell dynamics

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DOI

https://doi.org/10.1038/ni.3578

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