Letter | Published:

EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells

Nature volume 533, pages 110114 (05 May 2016) | Download Citation

Abstract

T follicular helper (Tfh) cells are a subset of T cells carrying the CD4 antigen; they are important in supporting plasma cell and germinal centre responses1,2. The initial induction of Tfh cell properties occurs within the first few days after activation by antigen recognition on dendritic cells, although how dendritic cells promote this cell-fate decision is not fully understood1,2. Moreover, although Tfh cells are uniquely defined by expression of the follicle-homing receptor CXCR5 (refs 1, 2), the guidance receptor promoting the earlier localization of activated T cells at the interface of the B-cell follicle and T zone has been unclear3,4,5. Here we show that the G-protein-coupled receptor EBI2 (GPR183) and its ligand 7α,25-dihydroxycholesterol mediate positioning of activated CD4 T cells at the interface of the follicle and T zone. In this location they interact with activated dendritic cells and are exposed to Tfh-cell-promoting inducible co-stimulator (ICOS) ligand. Interleukin-2 (IL-2) is a cytokine that has multiple influences on T-cell fate, including negative regulation of Tfh cell differentiation6,7,8,9,10. We demonstrate that activated dendritic cells in the outer T zone further augment Tfh cell differentiation by producing membrane and soluble forms of CD25, the IL-2 receptor α-chain, and quenching T-cell-derived IL-2. Mice lacking EBI2 in T cells or CD25 in dendritic cells have reduced Tfh cells and mount defective T-cell-dependent plasma cell and germinal centre responses. These findings demonstrate that distinct niches within the lymphoid organ T zone support distinct cell fate decisions, and they establish a function for dendritic-cell-derived CD25 in controlling IL-2 availability and T-cell differentiation.

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References

  1. 1.

    & T-cell subsets in the germinal center. Immunol. Rev. 252, 146–155 (2013)

  2. 2.

    T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529–542 (2014)

  3. 3.

    et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 (1998)

  4. 4.

    et al. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J. Immunol. 179, 5099–5108 (2007)

  5. 5.

    et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J. Exp. Med. 208, 1377–1388 (2011)

  6. 6.

    , , , & STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209, 243–250 (2012)

  7. 7.

    et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847–856 (2012)

  8. 8.

    et al. STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function. J. Biol. Chem. 287, 11234–11239 (2012)

  9. 9.

    , & Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nature Immunol. 13, 405–411 (2012)

  10. 10.

    , & Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13–25 (2013)

  11. 11.

    , , & EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009)

  12. 12.

    et al. Oxysterols direct immune cell migration via EBI2. Nature 475, 524–527 (2011)

  13. 13.

    et al. Oxysterols direct B-cell migration through EBI2. Nature 475, 519–523 (2011)

  14. 14.

    et al. T follicular helper cells have distinct modes of migration and molecular signatures in naive and memory immune responses. Immunity 42, 704–718 (2015)

  15. 15.

    et al. Expression of the zinc finger transcription factor zDC (Zbtb46, Btbd4) defines the classical dendritic cell lineage. J. Exp. Med. 209, 1153–1165 (2012)

  16. 16.

    et al. Cutting edge: dendritic cell-restricted antigen presentation initiates the follicular helper T cell program but cannot complete ultimate effector differentiation. J. Immunol. 187, 1091–1095 (2011)

  17. 17.

    & EBI2-mediated bridging channel positioning supports splenic dendritic cell homeostasis and particulate antigen capture. eLife 2, e00757 (2013)

  18. 18.

    et al. Splenic dendritic cells survey red blood cells for missing self-CD47 to trigger adaptive immune responses. Immunity 43, 764–775 (2015)

  19. 19.

    , , , & ICOS-induced B7h shedding on B cells is inhibited by TLR7/8 and TLR9. J. Immunol . 177, 2356–2364 (2006)

  20. 20.

    et al. The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses. J. Immunol. 193, 2753–2763 (2014)

  21. 21.

    et al. Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J. Immunol . 135, 3172–3177 (1985)

  22. 22.

    et al. Soluble IL-2RA levels in multiple sclerosis subjects and the effect of soluble IL-2RA on immune responses. J. Immunol. 182, 1541–1547 (2009)

  23. 23.

    , , , & A variant of the Il2ra/Cd25 gene predisposing to graves’ disease is associated with increased levels of soluble interleukin-2 receptor. Scand. J. Immunol. 74, 496–501 (2011)

  24. 24.

    , , & Soluble IL-2Rα (sCD25) exacerbates autoimmunity and enhances the development of Th17 responses in mice. PLoS ONE 7, e47748 (2012)

  25. 25.

    , & Does the IL-2 receptor α chain induced on dendritic cells have a biological function? Int. Immunol. 10, 237–240 (1998)

  26. 26.

    et al. Role of CD25+ dendritic cells in the generation of Th17 autoreactive T cells in autoimmune experimental uveitis. J. Immunol. 188, 5785–5791 (2012)

  27. 27.

    et al. Infection of myeloid dendritic cells with Listeria monocytogenes leads to the suppression of T cell function by multiple inhibitory mechanisms. J. Immunol. 181, 4976–4988 (2008)

  28. 28.

    & Expression of functional IL-2 receptors on mature splenic dendritic cells. Eur. J. Immunol. 30, 1453–1457 (2000)

  29. 29.

    et al. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nature Med. 17, 604–609 (2011)

  30. 30.

    & The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nature Rev. Immunol. 15, 283–294 (2015)

  31. 31.

    et al. Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses. Immunity 37, 535–548 (2012)

  32. 32.

    , , & Impaired antibody responses but normal proliferation of specific CD4+ T cells in mice lacking complement receptors 1 and 2. Scand. J. Immunol. 70, 77–84 (2009)

  33. 33.

    et al. Distinct in vivo dendritic cell activation by live versus killed Listeria monocytogenes. Eur. J. Immunol. 35, 1463–1471 (2005)

  34. 34.

    , , & Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007)

  35. 35.

    et al. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J. Exp. Med. 203, 1081–1091 (2006)

  36. 36.

    & Identification of mouse T follicular helper cells by flow cytometry. Methods Mol. Biol. 1291, 3–11 (2015)

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Acknowledgements

We thank C. Allen, M. Ansel, T. Defranco, M. Muschen and S. Sanjabi for mice, J. An for help with the mouse colony, Y. Xu for help with quantitative PCR, and A. Abbas and M. Barnes for comments on the manuscript. J.G.C. is an investigator of the Howard Hughes Medical Institute. E.L. is supported by the University of California, San Francisco, Biomedical Sciences (BMS) Graduate program and the National Science Foundation (grant number 1144247). This work was supported in part by National Institutes of Health grant AI40098.

Author information

Author notes

    • Tangsheng Yi

    Present address: Department of Discovery Immunology, Genentech, South San Francisco, California 94080, USA.

Affiliations

  1. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 94143, USA

    • Jianhua Li
    • , Erick Lu
    • , Tangsheng Yi
    •  & Jason G. Cyster
  2. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143, USA

    • Jianhua Li
    • , Erick Lu
    • , Tangsheng Yi
    •  & Jason G. Cyster
  3. Key Laboratory of Medical Molecular Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    • Jianhua Li

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Contributions

J.L. designed and performed experiments, interpreted the results and prepared the manuscript. E.L. performed several experiments including staining and quantitation of cell distribution in sections and helped prepare the manuscript. T.Y. performed experiments identifying the defects in EBI2 KO T cells. J.G.C. designed experiments, supervised research and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jason G. Cyster.

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https://doi.org/10.1038/nature17947

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