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


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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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.

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Author notes

    • Tangsheng Yi

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


  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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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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