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

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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Figure 1: EBI2 promotes positioning of newly activated CD4 T cells in the outer T zone.
Figure 2: Defective differentiation of EBI2-deficient T cells to follicular helpers.
Figure 3: T-cell EBI2 is required for CD4+ DC-mediated augmentation of Tfh cell induction.
Figure 4: DC CD25 expression reduces IL-2 signalling in activated CD4 T cells, favouring their differentiation to follicular helpers.

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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.

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Authors

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.

Corresponding author

Correspondence to Jason G. Cyster.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 EBI2 and 7α,25-OHC promote positioning of newly activated CD4 T cells in the outer T zone.

a, Flow cytometric analysis of EBI2 expression on splenic OTII T cells and endogenous B cells in transfer recipients at 0 and 12 h after SRBC-OVA immunization. EBI2 KO cells were used as a staining control. Left histograms show example FACS data and right panel shows summary data across the indicated time points as geometric mean fluorescence intensity (geoMFI). b, EBI2 expression on OTII and endogenous T cells in transfer recipients 2 days after saline or lipopolysaccharide-OVA immunization. Left histograms show example flow cytometric data and right panel shows summary geoMFI data for four mice. c, Summary geoMFI time course data of EBI2 expression on lymph node OTII T cells in transfer recipients at the indicated times after alum-OVA immunization. d, GFP expression in EBI2GFP/+ CD4 T cells that were unstimulated (naive) or treated with anti-CD3 plus anti-CD28 for 2 days. Left histogram shows example flow cytometric data and right panel shows summary geoMFI data for three mice. e, Ebi2 mRNA abundance in cells of the type in d, determined by RT–qPCR and shown relative to the naive cells. f, Migration of OTII T cells and endogenous cells to the indicated amounts of 7α,25-OHC in transwell assays. Cells were from unimmunized (0 h) or immunized (day 1, 2) transfer recipient mice in one experiment (left) or from 12 h immunized transfer recipients in a second experiment (right). Data are shown as percentage of input cells of each type that migrated. g, Immunofluorescence analysis of spleen showing the distribution of co-transferred WT CD45.1+ (red) and EBI2 het or KO (GFP+, green) OTII T cells and endogenous B cells (IgD, blue) at 12 h and 1 day after immunization. h, i, Immunohistochemical analysis of WT spleens (h) and inguinal lymph nodes (i) showing the distribution of transferred control (WT) or EBI2 deficient (KO) OTII CD45.1+ T cells (blue) and endogenous B cells (IgD, brown) at day 2 after lipopolysaccharide-OVA immunization (h) or day 1 after alum-OVA immunization (i). j, Immunohistochemical analysis of Cyp7b1, Ch25h or Hsd3b7 control (het, upper panels), or KO (lower panels) spleens showing the distribution of transferred WT OTII T cells (CD45.1, blue) and endogenous B cells (IgD, brown) at day 2 after SRBC-OVA immunization. k, CCR7 expression on WT and EBI2 KO OTII T cells in transfer recipient spleens at the indicated days after SRBC-OVA immunization. **P < 0.01 by ANOVA (a, c) or Student’s t-test (b, d, f). Data are representative of two (ai, k) or three (j) independent experiments with at least three (ac, k) or two (dj) mice per group (error bars (e), s.e.m.).

Extended Data Figure 2 Defective differentiation of EBI2-deficient T cells to follicular helpers.

a, ICOS and OX40 expression on WT, EBI2-deficient (KO) OTII and endogenous CD4 T cells in transfer recipient spleens two days after SRBC-OVA immunization. b, c, In vitro proliferation of WT and EBI2 KO T cells in response to anti-CD3 plus anti-CD28 in the presence of the indicated amounts of 7α,25-OHC, shown as violet tracer dye dilution profiles (b) and total CD4 T-cell numbers (c) at day 3 of culture. Numbers in b indicate frequency of cells that have undergone two or more divisions. d, Flow cytometric analysis of co-transferred WT and EBI2 KO OTII T cells for CXCR5 and intracellular Bcl6 expression at the indicated days after SRBC-OVA immunization. Numbers indicate frequency of cells in gated region. e, Summary of data of the type in d. Upper plot shows frequency and lower plot number of CXCR5+Bcl6hi OTII T cells. f, Il21 mRNA abundance in CXCR5+ PD-1hi control (Het) or EBI2 KO OTII T cells sorted from recipient spleens at day 3 after immunization with SRBC-OVA, determined by RT–qPCR and shown relative to the Het control. g, Frequency and number of CXCR5+ PD-1hi (left) or CXCR5+ Bcl6hi (right) WT and EBI2 KO OTII T cells in mice that received the cells as separate transfers, at day 3 after SRBC-OVA immunization. **P < 0.01 by ANOVA (e) or Student’s t-test (f, g). Data are representative of three (a, d, e, g) or two (b, c, f) independent experiments with at least three mice per group (error bars (f), s.e.m.).

Extended Data Figure 3 EBI2-deficient T cells support reduced plasma cell and germinal centre response.

a, Frequency and number of CXCR5+PD-1hi CD4+ control (WT) and EBI2 KO OTII T cells in spleens of day 3 Listeria-OVA immunized transfer recipients. b, PD-1 and CXCR5 flow cytometric analysis of control (Het) and EBI2 KO polyclonal CD4 T cells co-transferred to OTII recipients, 8 days after immunization with unconjugated SRBCs. c, Summary of data of the type in b shown as CXCR5+PD-1hi cell frequency and number. d, Flow cytometric analysis for the germinal centre markers FAS and GL7 on endogenous B cells in OTII TCR transgenic mice that received no cells, control (HET) CD4 T cells or EBI2 KO CD4 T cells, or in WT B6 control mice, 12 days after immunization with unconjugated SRBCs. e, Summary of data from d shown as number of FAS+GL7+ germinal centre B cells. f, Flow cytometric analysis for CD138hi B220lo plasma cells (top) and intracellular IgM and IgG1 staining of these cells (bottom) in mice of the type in d. g, Summary of data from f shown as number of cells. h, Serum anti-SRBC antibody levels in mice of the type in d, determined by flow cytometric analysis of SRBCs stained with immune sera, plotted as geoMFI. i, j, Number of Fas+GL7+ germinal centre cells and CD138hiB220int plasma cells in Listeria-OVA immunized CD28 KO mice that had received control (het) or EBI2 KO OTII cells, analysed at day 5. **P < 0.01 by ANOVA (g, h) or Student’s t-test (a, e, c, i, j). Data are representative of two independent experiments with at least three mice per group.

Extended Data Figure 4 T-cell EBI2 is required for CD4+ DC-mediated augmentation of Tfh cell induction.

a, Frequency and number of CXCR5+PD-1hi OTII T cells in μMT recipients determined by flow cytometric analysis. b, Flow cytometric analysis for CD11c and MHC class II on splenocytes from Zbtb46-DTR mice treated with saline or DT for 1 day. Graph shows summary data for DC number in four mice of each type. c, Frequency and number CXCR5+PD-1hi WT and EBI2 KO OTII T cells in spleens from Zbtb46-DTR BM chimaeras treated with saline or diphtheria toxin (DT), at day 3 after immunization with SRBC-OVA. d, Immunohistochemical analysis of spleen sections from WT mice without immunization (saline) or SRBC immunized for the indicated times, stained to detect IgD+ B cells (blue) and DCIR2+ DCs (brown). e, Immunohistochemical analysis of spleen sections from recipients of WT or EBI2 KO OTII T cells at 12 h and 1 day after immunization SRBC-OVA immunization, stained for OTII CD45.1+ T cells (blue) and DCIR2+ DCs (brown). f, Immunohistochemical analysis of spleen sections from WT:Zbtb46-DTR or CCR7 KO:Zbtb46-DTR mixed BM chimaeras treated with DT, at day 2 after immunization. g, Frequency and number of CXCR5+PD-1hi WT and EBI2 KO OTII T cells in spleens from WT:Zbtb46-DTR (control) or CCR7 KO:Zbtb46-DTR mixed BM chimaeras treated with DT, at day 3 after immunization. h, Frequency and number of CXCR5+PD-1hi control (het) and EBI2 KO co-transferred OTII T cells in spleens of CD47 KO recipients at day 3 after SRBC-OVA immunization. i, Number of total and CD4+ DC in spleens from Irf4f/f CD11c-Cre or + mice. j, As for g but in Irf4f/f CD11c-Cre or + recipient mice. k, As for g but in Batf3 KO recipient mice. l, ICOSL surface levels for DCs from mice immunized 12 h earlier with saline or SRBCs and treated with control or ICOS blocking antibody. m, ICOSL surface levels for CD4+ or CD8+ DCs from CD28 KO mice immunized 12 h earlier with saline or SRBCs. n, Il6 and Tgfβ mRNA abundance in sorted CD4+ and CD8+ splenic DCs from mice treated with saline or SRBC 6 h earlier, determined by RT–qPCR, shown relative to the control CD8+ DC. **P < 0.01 by ANOVA (g, k) or Student’s t-test (ac, i, j, m). Data are representative of three (ae) or two (fn) independent experiments with at least three (ac, gn) or two (df) mice per group (error bars (n), s.e.m.).

Extended Data Figure 5 DCs produce membrane and soluble CD25 and inhibit IL-2R signalling.

a, Heat map of RNA-seq data from sorted CD4+ splenic DC showing the top 15 most induced genes at 1 h after SRBC versus saline immunization. b, CD25 surface levels in CD11b+ migratory and resident DCs from lymph nodes of mice immunized with saline or alum-OVA 2 days earlier. Graph on right shows summary data for total number of migratory CD25+ DCs. c, Immunohistochemical analysis of spleen sections from TCRβδ KO mice immunized 1 day earlier with saline or SRBC, stained to detect IgD (blue) and CD25 (brown). d, e, CD122 (Il2rb) mRNA determined by RT–qPCR (d) and surface staining (e) on the indicated cell types isolated from spleens of WT OTII T-cell recipients at day 0, 1 and 2 after SRBC-OVA immunization. Transcript data are plotted relative to the signal in CD4+ DCs at day 0. f, Intracellular flow cytometric analysis of pSTAT5 in CD4+ DCs or, as a positive control CD4+ T cells, that were untreated or incubated with IL-2 (200 pg ml−1) or, as a further positive control, GM-CSF (100 pg ml−1). g, Il2 mRNA in control (Het) and EBI2 KO OTII T cells isolated from recipient mice at the indicated times after SRBC-OVA immunization. h, Intracellular flow cytometry for IL-2 in cells of the type in f at 0, 12 and 24 h. Percentages show mean (±s.e.m.) for three mice at each time point. i, Flow cytometric analysis of CD25 expression on co-transferred WT and EBI2 KO OTII T cells in WT recipients at the indicated days after SRBC-OVA immunization. j, Prdm1 (encoding Blimp1) transcript levels in sorted CXCR5+PD-1hi control (het) and EBI2 KO OTII T cells from SRBC-OVA immunized mice at day 3, plotted relative to the mean level in the Het group. k, Summary of pSTAT5 staining data for OTII T cells from mice immunized 1 day earlier with SRBC-OVA, incubated with the indicated amounts of 7α,25-OHC plus IL-2 (200 pg ml−1) for 1 h. l, Flow cytometry of pSTAT5 in CD25+ (regulatory) T cells exposed to the indicated amounts of IL-2 that had been pre-mixed with supernatants (s/n) from 8 h cultures of splenic CD4+ DCs from WT or CD25 KO mice immunized with saline or SRBCs 1 day before. Graph on right shows summary data from one experiment. **P < 0.01 by ANOVA (b, l) or Student’s t-test (j). Data are representative of one (a) or two (bl) independent experiments with at least two (a) or three (bl) mice per group (error bars (g, j), s.e.m.).

Extended Data Figure 6 DC CD25 expression reduces IL-2 signalling in activated CD4 T cells, favouring their differentiation to follicular helpers.

a, Diagram of CD25 KO:Zbtb46-DTR BM chimaera generation and time line of experiment. DTx, DT treatment. bd, Numbers (b), surface marker expression (c) and outer T zone positioning (d) of CD4+ DCIR2+ DCs in WT:Zbtb46-DTR and CD25 KO:Zbtb46-DTR mixed BM chimaeras pre-treated with DT, at day 1 after saline or SRBC immunization. e, Number of Foxp3+ CD25+ regulatory T cells in mice of the type in b except that the mice were immunized for three days. f, Immunohistochemical analysis of spleen sections from mice of the type in b, stained to detect IgD (blue) and CD25 (brown). g, h, Frequency and number of CXCR5+PD-1hi control (EBI2 Het) and EBI2 KO OTII T cells in spleens (g) or lymph nodes (h) from WT:Zbtb46-DTR or CD25 KO:Zbtb46-DTR mixed BM chimaeras pre-treated with saline or DT, at day 3 after immunization with Listeria-OVA (g) or alum-OVA (h). i, j, Flow cytometric analysis for HEL-binding CD138+ plasma cells (i) and HEL-binding GL7+ Fas+ germinal centre B cells (j) in spleens from WT:Zbtb46-DTR (control) or CD25 KO:Zbtb46-DTR mixed BM chimaeras that had received Hy10 B cells and been treated with DT, at day 5 after immunization with HEL-SRBC. k, Soluble CD25 detected by ELISA in spleen extracts taken from 12 h SRBC immunized mice, at day 1 after saline or recombinant CD25 treatment. **P < 0.01 by Student’s t-test (h, k). Data are representative of two independent experiments with at least three (b, c, g–k) or two (d, f) mice per group (error bars (k), s.e.m.).

Extended Data Figure 7 Model of how EBI2-dependent positioning of activated T cells in association with CD25+ DCs in the outer T zone favours Tfh cell differentiation.

Initially, cognate T cells throughout the T zone are activated by antigen recognition and promptly start upregulating EBI2 and making IL-2. EBI2 guides cells to the 7α,25-OHC high outer T zone and in this location they interact with activated DCs producing membrane and shed CD25 that binds and quenches IL-2. This limits IL-2R signalling on the T cell via pSTAT5 and allows induction of Bcl6 by other inputs such as ICOSL. T cells that lack EBI2 or remain in the inner T zone for other reasons are exposed to autocrine IL-2 and this induces Blimp1, a repressor of Bcl6 (ref. 2), disfavouring the Tfh cell fate.

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Li, J., Lu, E., Yi, T. et al. EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells. Nature 533, 110–114 (2016). https://doi.org/10.1038/nature17947

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