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The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood

Nature Immunology volume 14, pages 152–161 (2013)Cite this article

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Abstract

CD4+CXCR5+Foxp3+ follicular regulatory T cells (TFR cells) inhibit humoral immunity mediated by CD4+CXCR5+Foxp3− follicular helper T cells (TFH cells). Although the inhibitory receptor PD-1 is expressed by both cell types, its role in the differentiation of TFR cells is unknown. Here we found that mice deficient in PD-1 and its ligand PD-L1 had a greater abundance of TFR cells in the lymph nodes and that those TFR cells had enhanced suppressive ability. We also found substantial populations of TFR cells in mouse blood and demonstrated that TFR cells in the blood homed to lymph nodes and potently inhibited TFH cells in vivo. TFR cells in the blood required signaling via the costimulatory receptors CD28 and ICOS but were inhibited by PD-1 and PD-L1. Our findings demonstrate mechanisms by which the PD-1 pathway regulates antibody production and help reconcile inconsistencies surrounding the role of this pathway in humoral immunity.

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Figure 1: PD-1 signaling in Foxp3 Treg cells limits generation of TFR cells.
Figure 2: PD-1-deficient TFR cells have altered expression of activation markers.
Figure 3: PD-1-deficient TFR cells are able to home to GCs.
Figure 4: PD-1-deficient TFR cells have enhanced regulatory ability.
Figure 5: PD-1 controls circulating TFR cells in the blood.
Figure 6: PD-L1 controls TFR cells in the blood but PD-L2 does not.
Figure 7: TFR cells in the blood require costimulation via ICOS and CD28.
Figure 8: PD-1-deficient blood TFR cells more potently regulate antibody in vivo.

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Acknowledgements

We thank R. Ortega, C. Armet, F. Gonzalez, N. Chouaki, D. Brown and S. Lee for technical assistance; G. Freeman for comments on the manuscript; and M. Carroll (Harvard Medical School) for the mouse anti-NP standard. Supported by the US National Institutes of Health (T32 AI070085 to P.T.S.; and R01 AI40614, P01 78897 and R37 AI38310 to A.H.S.).

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Authors and Affiliations

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

    Peter T Sage, Loise M Francisco & Arlene H Sharpe

  2. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Peter T Sage & Christopher V Carman

  3. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Loise M Francisco & Arlene H Sharpe

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  1. Peter T Sage
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Contributions

P.T.S. did all experiments; P.T.S. and A.H.S. designed the studies, analyzed and interpreted the results and wrote the manuscript; and L.M.F. and C.V.C. provided technical help and edited the manuscript.

Corresponding author

Correspondence to Arlene H Sharpe.

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Sage, P., Francisco, L., Carman, C. et al. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol 14, 152–161 (2013). https://doi.org/10.1038/ni.2496

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