Abstract
Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of TFH cell survival remains unclear. Here we report that TFH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for TFH cell survival. The deletion of GPX4 in T cells selectively abrogated TFH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased TFH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium–GPX4–ferroptosis axis in regulating TFH homeostasis, which can be targeted to enhance TFH cell function in infection and following vaccination.
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All data are provided in the article and its supplementary files or from the corresponding author upon reasonable request. Source data are provided with this paper.
Change history
04 October 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41590-021-01063-4
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Acknowledgements
We thank the Imaging and Cytometry Facility and the Biomolecular Research Facility at the John Curtin School of Medical Research and the Biomolecular Research Facility at Translational Research Institute for technical support; the Centre of Advanced Microscopy at the Australian National University for the scientific and technical assistance for TEM; R. Steptoe and Y. Zhan for the hybridoma cell line; D. Gray for Foxp3-GFP reporter mice; S. Ming Man for Casp1/11−/− mice; J. Adams for Bcl2-transgenic mice; H. Wu and Q. Li for tissue imaging and E. Bartlett for reading the manuscript. This study was supported by Australian National Health and Medical Research Council project GNT1085509; the Bellberry-Viertel Senior Medical Research fellowship; National Natural Science Foundation of China grants 81630024, 81920108011 and 82071792; Health Commission of Hubei Province Scientific Research Project WJ2019H136 and WJ2019H137; Natural Science Foundation of Shandong Province ZR2020ZD41 and ZR2019BB080; Taishan Scholars Program of Shandong Province; and a China Scholarship Council scholarship 201706160045.
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Y. Yao. planned and performed most experiments with major support from Z.A.C. and H.Z.. Y.B.W. performed plasma selenium levels analysis. C.L.C., M.Z., Z.Q.L., M.Z.Z., C.Q., Y.M.W., Y.K.D., N. Wang, C.S., C.L.G., H.B.S., H.L.Y. and W.T.Z. participated in the human trial. J.V. helped with imaging. N. Wu. and A.H. helped with flow cytometry. H.S.O., H.W., F.V.M., Z.H.Y., Y. Yang and P.C.Z. participated in animal experiments; Q.X.Z., J.D. and N.S. helped with human cell sorting and cell culture. N.Q.W. participated in animal experiments and helped with data analysis. W.H.Z., J.B.H., Y.X., J.F., D.M.L., M.X. and L.Y. participated in discussion and human study. D.Y. and Z.L. designed the study and supervised the project.
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Extended data
Extended Data Fig. 1 The cell death of TFH cells is not regulated by apoptosis or pyroptosis.
a, b, As indicated by the schematic of bone marrow (BM) reconstitution to generate chimeric mice, indicated mixtures of BM cells were transferred into lethally irradiated Rag1–/– recipients. After 6 weeks, chimeric mice were subcutaneously immunized with NP-OVA in Alum. b, At day 14 post immunisation, frequencies of TFH and BGC cells derived from WT or transgenic were analysed by flow cytometry (n = 5 for control and n = 6 for Bcl-2-Tg and Casp1/11-KO). c, C57/BL6/J mice were subcutaneously immunized with NP-OVA in Alum. Cell size of TFH and non-TFH cells at day 7 post immunisation was analysed by flow cytometry (n = 6). d, Congenic marked C57/BL6/J mice were adoptively transferred of OT-II cells and then intraperitoneally immunised with OVA in Alum. At day 7 post immunisation, cell size of TFH and non-TFH OT-II cells was analysed by flow cytometry (n = 6). e, Mice were intraperitoneally immunised with SRBC, TFH and non-TFH cells were sorted at day 8 post immunisation. Lipid ROS production in TFH and non-TFH cells was analysed by flow cytometry using C11-BODIPY (n = 5). f, Flow cytometric analysis of lipid ROS production in purified tonsillar TFH and non-TFH cells (n = 4). Each dot represents one individual. g, Purified naïve CD4+ T, non-TFH, and TFH cells from human tonsils were stimulated with αCD3/CD28 and treated with different doses of RSL-3 or H2O2 for 12 h. Frequencies of Annexin V–7-AAD– viable cells were assessed by flow cytometry (n = 3). Data are representative of three independent experiments. For b, g, data are expressed as mean ± SEM. Data are analysed by two-sided Student’s t-test (b), paired-sample t-test (c-f), or one-way ANOVA (g). For g, bonferroni correction was used to adjust the significance level by using a value of 0.017 for each comparison. Data are representative of three (c–e) experiments with at least three mice per group.
Extended Data Fig. 2 Characterisation of GPX4-deficient T cells in mice.
a, GPX4 protein expression in splenic CD4+ cells from Cd4-CreNegGpx4flox/flox (WT) and Cd4-CreGpx4flox/flox (T-KO) mice were analysed by flow cytometry (n = 5). b, c, Naïve CD4+ T cells were purified from WT and T-KO mice and cultured in 2-Mercaptoethanol-deprived culture medium. The frequencies of Annexin V–7-AAD– viable cells (b) and lipid ROS production (c) were assessed by flow cytometry at indicated time points (n = 3). Data are representative of three independent experiments. d, Naïve CD4+ T cells from WT or T-KO mice were cultured for 2 h and imaged by transmission electron microscopy. Blue arrow indicates mitochondria from WT mice, and the red arrow indicates shrunken and damaged mitochondria from T-KO mice. Scale bars, 1 μm. The area of each mitochondrion was calculated using ImageJ. Each dot represents one mitochondrion. Box plots shows medians and the extent from the 25th to 75th percentiles, with error bars covering the data range. e-g, Flow cytometric analysis of T cell subsets of WT and T-KO mice at 8-weeks old. Total numbers of thymocytes (e) and splenic cells (f) were quantified and CD44 and CD62L expression on splenic CD4+ T cells (g) were analysed (n = 5). h–l, WT and T-KO mice were subcutaneously immunised with NP-OVA in Alum (n = 5 for WT and n = 3 for T-KO). h, At day 7 post immunisation, frequencies of CD44+, CD69+, and Ki-67+ cells in CD4+ T cells of draining popliteal lymph nodes were analysed by flow cytometry. i, TFR cells were analysed at day 7 and 14 after immunisation. Gata3 (j) and Rorγt (k) expression in CD4+Foxp3– cells were analysed by flow cytometry. l, TREG cells were analysed at day 7 and 14 after immunisation. Numbers indicate the frequency of cells in the gated region. For a, e–l, each dot represents one mouse. Data are presented as mean ± SEM and analysed by two-sided Student’s t-test (a, e–l). For a, e–l, data are representative of two independent experiments with at least three mice per group.
Extended Data Fig. 3 Vitamin E rescues TFH cell from ferroptosis induced by GPX4 deletion.
a–d, Cd28–/– mice were adoptively transferred of WT or T-KO OT-II cells and then intraperitoneally immunised with OVA in Alum. At day 10 post immunisation, recipient CD8+ T (a) and Foxp3+ TREG (b) cells and OT-II TREG (c) and TFR (d) cells in spleen were analysed by flow cytometry (n = 5). e, f, Cd28–/– mice were adoptively transferred OT-II cells from T-KO mice, subcutaneously immunised with NP-OVA in Alum and treated every 2 days with control or Vitamin E (100 mg/kg) from day 1–9 post immunisation. f, At day 10, frequencies and numbers of CXCR5+Bcl-6+ TFH in popliteal lymph nodes were analysed by flow cytometry (n = 5). Numbers indicate the frequency of cells in the gated region. Each dot represents one mouse. Data are presented as mean ± SEM and analysed by two-sided Student’s t-test. Data are representative of two experiments with at least five mice per group.
Extended Data Fig. 4 High cytosolic ROS expression in TFH cells.
a, Flow cytometric analysis of cytosolic ROS production in purified CD44+CD25–CXCR5highPD-1high TFH and CD44+CD25–CXCR5–PD-1– non-TFH cells from spleen of SRBC-immunised mice at day 8 post immunisation using CM-H2DCFDA (n = 3). Each dot represents one mouse. b, Comparison of cytosolic ROS levels between circulating CD25–/lowCD127–/+CD45RA–CXCR5+ TFH and CD25–/lowCD127–/+CD45RA–CXCR5– non-TFH effector cells in human peripheral blood (n = 5). Each dot represents a single blood donor. c, Comparison of cytosolic ROS levels between CD45RA–CXCR5high TFH and CD45RA–CXCR5– non-TFH effector cells in human tonsils (n = 10). Each dot represents a single tonsil donor. Data are analysed by paired-sample t-test.
Extended Data Fig. 5 Comparing the levels of ferroptosis-related factors in TFH and non-TFH cells.
a, Gene expression related to cytosolic and lipid ROS and ferroptosis in TFH and non-TFH cells in human and mice. Data were obtained by analysing published RNA-seq data. b, Glutathione (GSH) levels in purified tonsillar CD4+CD19–CD25–CD45RA–CXCR5high TFH and CD4+CD19–CD25–CD45RA–CXCR5– non-TFH cells were detected by ELISA (n = 3). c, Total Fe levels in purified tonsillar TFH and non-TFH cells were analysed by ICP-AES (n = 4). d, Fe2+ levels in tonsillar TFH and non-TFH cells were analysed by flow cytometry using FerroOrange (n = 5). e, Total SFAs and the ratio of total PUFAs/total MUFA in purified tonsillar TFH and non-TFH cells were analysed by GC-MS (n = 4). For b-e, each dot represents a single tonsil donor. Data are analysed by paired-sample t-test.
Extended Data Fig. 6 Intensified TCR stimulation induces high ROS production in TFH cells.
a, Purified naïve CD4+ T cells were stimulated with αCD3/CD28 in 2-Mercaptoethanol-deprived culture medium, and cytosolic ROS production was assessed by flow cytometry at 24 and 72 h after incubation (n = 3 for each dose). Data are represented as fold change by normalizing to no stimulation and representative of three independent experiments. b, c, Purified CD4+CD19–CD25–CD45RA–CXCR5high TFH cells from human tonsils were cultured with indicated cytokines or stimulators in the absence (b) or presence (c) of 3 µM RSL-3 in 2-Mercaptoethanol-deprived culture medium for 12 h. Lipid ROS levels and frequencies of 7AAD– viable cells were analysed by flow cytometry (n = 3). Data are representative of three independent experiments. d, Mice were subcutaneously immunised with NP-OVA in Alum. Flow cytometric analysis of cytosolic ROS production in CD44+CD25–CD19–CXCR5highPD-1high TFH and FAS+GL-7+B220+ BGC cells at day 10 post immunisation (n = 6). Each dot represents one mouse. Data are representative of two independent experiments with at least five mice per group. Data are presented as mean ± SEM (a–c) and analysed by two-sided Student’s t-test (a–c) or paired-sample t-test (d).
Extended Data Fig. 7 Ferrostatin-1 rescues TFH cells in mice immunised with NP-OVA.
a–d, Cd4-CreGpx4wt/wt (WT) and Cd4-CreGpx4wt/flox (T-HET) mice were subcutaneously immunised with NP-OVA in Alum. At day 14 post immunisation, the frequencies of CD3+ and CD4+ T cells (a), CD44, CD69, and Ki-67 expression by CD4+ T cells (b), frequencies of Foxp3+ TREG and Bcl-6+Foxp3+ TFR cells (c), and IFNγ, IL-4, and IL-17A production by CD44+CD25–CXCR5–PD-1– non-TFH cells (d) were analysed by flow cytometry (n = 5). e–g, As the schematic of experiment design (e), mice were adoptively transferred OT-II cells, intraperitoneally immunised with NP-OVA in Alum and treated daily with DMSO (control) or Ferrostatin-1 (10 mg/kg) from day 7–9 post immunisation. At day 10, frequencies of donor OT-II cells in total CD4+ T cells (f) and frequencies and numbers of TFH and non-TFH OT-II cells (g) in spleen were analysed by flow cytometry (n = 5). h–l, C57/BL6/J mice were intraperitoneally immunised with NP-OVA in Alum and treated every 2 days with DMSO (control) or Ferrostatin-1 (2 mg/kg) s.c. from day 5–13 post immunization. At day 14, CD44+Foxp3–CXCR5– non-TFH cells (i), Ki-67 expression by non-TFH cells (j), IFNγ, IL-4, and IL-17A production by non-TFH cells (k), Foxp3+ TREG cells, and Bcl-6+Foxp3+ TFR cells (l) in draining popliteal lymph nodes were analysed by flow cytometry (n = 6). Each dot represents one mouse. Data are presented as mean ± SEM and analysed by two-sided Student’s t-test. Data are representative of two experiments with at least four mice per group.
Extended Data Fig. 8 Selenium supplementation promotes TFH cell responses in mice.
a–g, C57/BL6/J mice were fed with water containing methionine (Met, 1 mg/L) or selenomethionine (Se-Met, 1 mg/L) one month before immunisation with NP-OVA in Alum. b, Selenoprotein P (SelP) and glutathione peroxidase 3 (GPX3) levels in serum were measured by ELISA at indicated time points (n = 6). At day 7 and 14 post immunisation, Ki-67 expression in TFH cells (c), Annexin V and cytosolic ROS staining of non-TFH (d), IFNγ, IL-4, and IL-17A production by non-TFH cells (e), Foxp3+ TREG cells (f), and CD44+Foxp3+Bcl-6+ TFR cells (g) in popliteal lymph nodes were analysed by flow cytometry (n = 6). h-l, C57/BL6/J mice were fed with adequate selenium (0.15 mg Se/kg) or high selenium (1 mg Se/kg) diets one month before the immunisation with NP-OVA in Alum. i, Selenoprotein P (SelP) levels in serum were measured by ELISA at indicated time points (n = 5). At day 14 post immunisation, TFH (j) and BGC cells (k) in popliteal lymph nodes were analysed by flow cytometry (n = 5). l, Serum NP23- and NP2-binding IgG1 were measured by ELISA (n = 5). Numbers indicate frequency of cells in gated region. Each dot represents one mouse. Data are presented as mean ± SEM and analysed by two-sided Student’s t-test. Data are representative of three experiments with at least five mice per group.
Extended Data Fig. 9 The gating strategy to analyse peripheral CD4+ T cell subsets in human blood.
Within viable CD3+CD8–CD4+ T cells, TREG cells were defined as CD25highCD127low cells, circulating TFH cells as CD25–/lowCD45RA–CXCR5+ cells, activated TFH cells as ICOShighPD-1high or PD-1high CCR7low TFH cells, activated non-TFH cells as CXCR5–ICOShighPD-1high cells, TH1 cells as CD25–/lowCD45RA–CXCR3+CCR6–CCR7lowCCR4– cells, TH2 cells as CD25–/lowCD45RA–CXCR3–CCR6–CCR7lowCCR4+ cells, and TH17 cells as CD25–/lowCD45RA–CXCR3–CCR6+CCR7–CCR4+ cells.
Extended Data Fig. 10 Changes in circulating T cell subsets after selenium supplementation.
a, Young healthy subjects were enrolled and randomised into selenium supplementation (200 μg/day) and control groups. Thirty days after the start of supplementation, all subjects received seasonal influenza vaccination, and peripheral blood was collected at baseline (day −30), day 0 (before vaccination), day 7 (day 7 post vaccination), and day 30 (day 30 post vaccination). b, Frequency of circulating CXCR5+CCR7lowPD-1high TFH cells in total CD4+ T cells were analysed by flow cytometry (n = 29 for control and n = 28 for selenium). Changes of TFH cells at the indicated time points were normalised to the baseline and represented as fold changes. c–e, Frequencies and fold changes normalised to the baseline of indicated populations were analysed by flow cytometry (n = 29 for control and n = 28 for selenium). f, g, IL-21 production by circulating CD25–/lowCD45RA–CXCR5+ TFH cells (f) and IFNγ, IL-4, and IL-17A production by CD25–/lowCD45RA–CXCR5– non-TFH cells (g) were analysed by flow cytometry (n = 23 for control and n = 24 for selenium). Numbers indicate the frequency of cells in the gated region. Each dot represents one individual. Data are presented as median and interquartile range and analysed by Mann-Whitney U test.
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Yao, Y., Chen, Z., Zhang, H. et al. Selenium–GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol 22, 1127–1139 (2021). https://doi.org/10.1038/s41590-021-00996-0
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DOI: https://doi.org/10.1038/s41590-021-00996-0
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