Abstract
TRPV1 is a Ca2+-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4+ T cells, where it acted as a non–store-operated Ca2+ channel and contributed to T cell antigen receptor (TCR)-induced Ca2+ influx, TCR signaling and T cell activation. In models of T cell–mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4+ T cells recapitulated the phenotype of mouse Trpv1−/− CD4+ T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.
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Acknowledgements
We thank C. Conche and K. Sauer for help with measurements of Ca2+; A. Patapoutian (The Scripps Research Institute) for Chinese hamster ovary cells transfected to express TRPV1; E. Garcia and T. Snutch for access to electrophysiological equipment; J. Lee and C. Quinley for discussions; M. Scholl for animal breeding; T. Rambaldo for cell sorting; S. Shenouda for tissue processing; N. Varki and L. Eckmann for help with histological evaluations; and J. Santini for technical assistance with confocal imaging at the Neuroscience microscopy shared facility of the University of California San Diego (supported by the National Institute of Neurological Disorders and Stroke of the US National Institutes of Health (P30 NS047101)). Supported by the US National Institutes of Health (U01 AI095623 and P01 DK35108 to E.R., and AI083432 to Y.G.), the Canadian Institutes of Health Research (MOP-102698 to W.A.J.), the Broad Foundation (IBD-0342R to E.R.), the Crohn's & Colitis Foundation of America (SRA 3038 to E.R., RFA 3574 to S.B., and RFA 2927 to P.R.d.J.), the European Molecular Biology Organization (ALTF 288-2009 to S.B.), the Fulbright Association (S.B.), the Philippe Foundation (S.B.) and the Japan Society for the Promotion of Science (Y.A.-N.).
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S.B., P.R.d.J., A.F. and E.R. designed the study; S.B., Y.A.-N., P.R.d.J., K.T., L.A., T.Y., T.H., X.L. and J.M.G.-N. performed most of the in vitro and in vivo experiments; S.B. measured the Ca2+ flux by flow cytometry, with the technical assistance of X.L. and G.F.; S.S. and Y.G. performed single-cell Ca2+ imaging in mouse CD4+ T cells; S.B. and J.L., with the help of H.D., performed single-cell Ca2+ imaging in Jurkat cells; L.L.N., H.X., S.R.S. and W.A.J. planned and designed the electrophysiological assays, L.L.N., H.X. and S.R.S. performed these assays, and L.L.N., H.X., S.R.S. and W.A.J. wrote the corresponding sections of the manuscript; R.T. and A.F. performed the human T cell experiments with TRPV1 antagonists; S.H. and M.C. took care of the mouse colony and genotyped the mice; L.L.N., H.X., S.R.S., W.A.J., S.B., Y.A.-N., P.R.d.J., T.Y., K.T., L.A., A.F. and E.R. analyzed and interpreted the data; S.B., E.R. and W.A.J. revised the manuscript for publication; and S.B. and E.R. wrote the manuscript.
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H. Dong is cofounder of AddexBio.
Integrated supplementary information
Supplementary Figure 1 TRPV1 is expressed and functional in CD4+ T cells.
(a) TRPV1 protein expression in mouse splenic (SP) CD4+ T cells, in human primary CD4+ T cells enriched from peripheral blood of healthy donors and in Jurkat human T cell line (clone E6.1) was determined by immunoblot on a 4-12% SDS-PAGE gel. Chinese hamster ovary (CHO) cells either control (Ctrl) or overexpressing rat TRPV1 (TRPV1+) were used as negative and positive controls, respectively. Doublets at ~95 kilodaltons (kDa) and 115 kDa correspond to the nonglycosylated and glycosylated forms of the TRPV1 channel and upper bands likely correspond to TRPV1 multimers40. (b) Confocal microscopy images of wild-type spleen CD4+ T cells stained with the DNA-binding dye DAPI (far left), goat anti-TRPV1 primary antibody and Alexa Fluor 546–conjugated anti-goat secondary antibody (middle left) and Alexa Fluor 488–conjugated anti-CD4 (middle right) antibodies, after pre-incubation of the TRPV1 antibody with its specific blocking peptide (TRPV1 IgG + peptide) or when using the isotype-matched control antibody immunoglobulin G (Ctrl IgG). Right, merged image; Scale bar = 5 μm. (c) Confocal microscopy images of CHO-Ctrl or CHO-TRPV1+ cells stained with the DNA-binding dye DAPI (left), goat anti-TRPV1 primary antibody and Alexa Fluor 546–conjugated anti-goat secondary antibody (middle); right, merged image. Scale bar = 10 μm. (d) Immunoblot analysis of TRPV1, β-actin (a cytosolic protein) and CD3ɛ (a plasma membrane protein) in total lysates or in plasma membrane protein fractions (methods, Biotinylation of Cell Surface Proteins) of Jurkat T cells either untransduced (wild-type, WT) or transduced with nontargeting control shRNA lentiviral particles (copGFP, GFP) or with TRPV1 shRNA lentiviral particles (TRPV1 knockdown, Trpv1-KD). (e) [Ca2+]i in wild-type and Trpv1-KD Jurkat T cells loaded with the calcium indicator Fura-2 AM and treated with 10 μM capsaicin (CAP, gray bar) in the presence of 2 mM CaCl2 (2 Ca; black bar), monitored by confocal imaging and presented as the ratio of Fura-2 emission at an excitation of 340 nm to that at 380 nm (340/380); right, quantification of the Ca2+-influx peak at left (mean ± s.e.m.); ****P <0.0001 (two-tailed Student t-test). Data are representative of two (b,c) or three (a,d-e) independent experiments.
Supplementary Figure 2 TRPV1 channel contributes to TCR-induced Ca2+ influx in CD4+ T cells.
(a) [Ca2+]i in wild-type (WT) and Trpv1–/– spleen CD4+ T cells loaded with the fluorescent Ca2+ indicator dye Indo-1 AM and stimulated with soluble anti-CD3 (10 μg/ml) and anti-CD28 (1 μg/ml) antibodies (α-CD3 + α-CD28) in Ca2+-free medium, with 5 mM CaCl2 (5 Ca) added to the extracellular medium during the acquisition, monitored by flow cytometry; results are presented as the ratio of Indo-1 AM emission at 405 nm to that at 510 nm (405/510). (b) Quantification of the Ca2+-influx profile shown in a. *P <0.05; ***P <0.001 (two-tailed Student t-test). (c) [Ca2+]i in WT and Trpv1–/– spleen CD4+ T cells as in a with 0.5 mM CaCl2 (0.5 Ca) added to the extracellular medium prior to α-CD3 + α-CD28 stimulation. (d) [Ca2+]i in WT and Trpv1–/– spleen CD4+ T cells as in a with α-CD3 + α-CD28 stimulation in RPMI medium (0.42 Ca). (e) [Ca2+]i in WT and Trpv1–/– spleen CD4+ T cells stimulated with soluble anti-CD3 (20 μg/mL) and anti-CD28 (2 μg/mL) Abs in Ca2+-free medium. (f) [Ca2+]i in WT and Trpv1-TG spleen CD4+ T cells stimulated as in a. (g) [Ca2+]i in WT and Trpv1-TG spleen CD4+ T cells stimulated with ionomycin (500 nM) in Ca2+-free medium, with 5 mM CaCl2 (5 Ca) added to the extracellular medium during the acquisition. (h) [Ca2+]i in WT and Trpv1–/– spleen CD4+ T cells stimulated with ionomycin (500 nM) or (i) thapsigargin (TPSG, 1 μM) in Ca2+-free medium, with 5 mM CaCl2 (5 Ca) added to the extracellular medium during the acquisition. (j) [Ca2+]i in WT and Trpv3–/– spleen CD4+ T cells stimulated as in a. (k) [Ca2+]i in WT CD4+ T cells loaded with Indo-1 AM and pretreated for 5 min with the TRPV1 antagonist I-RTX (0.1 or 1 μM) or the vehicle (veh; 0.1% dimethyl sulfoxide (DMSO)), then stimulated as in a.
Supplementary Figure 3 Cytokine profiles of Trpv1-TG CD4+ T cells and Trpv1–/– OT-II CD4+ T cells.
(a) Enzyme-linked immunosorbent assay (ELISA) of cytokines (horizontal axes) in wild-type (WT) and Trpv1-TG splenic CD4+ T cells stimulated for 24 h (IFN-γ, IL-17A, IL-2 and TNF) or 48 h (IL-10 and IL-4) with plate-bound anti-CD3 (10 μg/ml) and soluble anti-CD28 (1 μg/ml) (mean ± s.e.m. (n = 4 mice/group)); *P <0.05; **P <0.01; ***P <0.001 (two-tailed Student t-test). (b) Flow cytometry analysis of IFN-γ and IL-2 intracellular production in CD4+ T cells recovered from cocultures of OVA-loaded wild-type splenic CD11c+ DCs incubated for 5 d with OVA-specific Trpv1+/+ or Trpv1–/– OT-II splenic CD4+ T cells (n = 4 mice per group). Equal numbers of the CD4+ T cells recovered were restimulated or not for 5 h with anti-CD3 plus anti-CD28 before analysis. Representative panels of intracellular cytokine production in the different conditions are shown.
Supplementary Figure 4 Trpv1–/– and WT CD4+ T cells display similar apoptosis and proliferative response.
(a) Apoptosis of wild-type (WT) and Trpv1–/– spleen CD4+ T cells stimulated with anti-CD3 (10 μg/mL plate-bound) and anti-CD28 (1 μg/mL soluble) for 24 h as in Figure 5a, stained for CD4, annexin V and the DNA-intercalating dye 7-AAD and analyzed by flow cytometry. NS, not significant (two-tailed Student t-test) (mean ± s.e.m. (n = 3-4 mice/group)). (b) Proliferation of WT and Trpv1–/– spleen CD4+ T cells left unstimulated (US) or stimulated with anti-CD3 (10 μg/mL plate-bound) plus anti-CD28 (2 μg/mL soluble) (top panel) or PMA (25 ng/mL) and ionomycin (Iono, 500 nM) (bottom panel) for 72 h, stained with CD4 and CFSE and analyzed by flow cytometry. Representative panels of 3 independent experiments and percentages of cells that underwent 0-5 divisions are shown (mean ± s.e.m. (n = 3-4 mice/group)).
Supplementary Figure 5 Treatment with a TRPV1 antagonist reduces colitis severity in Il10–/– mice.
(a) Wasting disease in Il10–/– treated daily with the TRPV1 antagonist SB366791 (3 mg/kg, i.p) or with its vehicle (VEH) starting 3 days prior and daily during the 14 days of colitis induction by piroxicam (PXC). (b) Microcopy of colon sections from mice as in a, stained with hematoxylin and eosin. Scale bar, 1 mm (main images; 20× objective) or 100 μm (insets; 1× objective). (c) Colitis scores of the mice in a. (d) Enzyme-linked immunosorbent assay (ELISA) of IFN-γ and IL-17A production by spleen (SP) CD4+ T cells recovered from mice as in a, and restimulated for 24 h with anti-CD3 (10 μg/mL plate-bound) plus anti-CD28 (1 μg/mL soluble). (mean ± s.e.m. (n = 7-8 mice/group)). NS, not significant; **P <0.01 (two-tailed Student t-test). Data are representative of two independent experiments.
Supplementary Figure 6 Trpv1–/– naive CD4+ T cells have impaired colitogenic properties in an adoptive transfer model.
(a) Representative pictures of colons from Rag1–/– recipient mice 4 weeks after adoptive transfer of 3 × 105 wild-type (WT) or Trpv1–/– naive (CD4+CD45RBhiCD25–) T cells or a mixture of 3 × 105 WT naive CD4+ T cells plus 1.5 × 105 WT Treg (CD4+CD45RBloCD25+) cells (WT naive T cells + Treg) as in Figure 7d. (b) Colon length in each experimental group. (c) Microcopy of colon sections from mice as in a, stained with the DNA-binding dye DAPI, Alexa Fluor 546–conjugated anti-CD45 and Alexa Fluor 488–conjugated anti-Claudin-3 antibodies. Scale bar, 50 μm (40× objective). (d) Real-time PCR analysis of several proinflammatory cytokines (top panel) and chemokines (bottom panel) in colon samples. The Treg control group was used as reference and assigned to 1. (mean ± s.e.m. (n = 6-8 mice/group)). NS, not significant; *P < 0.05, **P < 0.01 and ***P < 0.001 (one-way analysis of variance (ANOVA) with post-hoc Bonferroni’s test).
Supplementary Figure 7 Trpv1–/– naive CD4+ T cells have impaired inflammatory responses in an adoptive transfer model.
Flow cytometry analysis of IFN-γ, IL-17A, FOXP3 and IL-10 intracellular expression in CD4+ T cells recovered from Rag1–/– recipient mice 4 weeks after adoptive transfer of 3 × 105 wild-type (WT) or Trpv1–/– naive (CD4+CD45RBhiCD25–) T cells as in Figure 7d, and restimulated for 5 h with anti-CD3 (10 μg/mL plate-bound) plus anti-CD28 (1 μg/mL soluble). Percentages and numbers of IFN-γ+, IL-17A+, FOXP3+ or IL-10+ CD4+ T cells in (a) the spleen (SP), (b,c) the mesenteric lymph nodes (MLN) and (d) the lamina propria (LP) are shown (pooled organs (n = 2 mice/group)).
Supplementary Figure 8 Deletion of Trpv1 decreases the capacity of naive CD4+ T cells to differentiate into TH1, TH2 and TH17 effector cells in vitro.
(a) Flow cytometry analysis of IFN-γ, IL-4, IL-17A and IL-10 intracellular production in CD4+ T cells recovered from cocultures of OVA-loaded wild-type bone marrow CD11c+ DCs incubated for 5 d with OVA-specific Trpv1+/+ or Trpv1–/– OT-II splenic CD4+ T cells (n = 4 mice per group) under Th1, Th2, Th17 and Treg-polarizing conditions (methods, in vitro T cell differentiation). Equal numbers of the CD4+ T cells recovered were restimulated or not for 5 h with anti-CD3 (10 μg/mL plate-bound) plus anti-CD28 (1 μg/mL soluble) before analysis. Representative panels of intracellular cytokine production in the different conditions are shown. (b) Percentages of CD4+IFN-γ+ (Th1), CD4+IL-4+ (Th2), CD4+IL-17A+ (Th17), and CD4+IL-10+ (Treg) cells as in a (mean ± s.e.m.). NS, not significant; *P <0.05 (two-tailed Student t-test).
Supplementary Figure 9 Trpv1-TG naive CD4+ T cells induce exacerbated colitis in an adoptive transfer model.
(a) Body weight of Rag1–/– recipient mice 4 weeks after adoptive transfer of 3 × 105 wild-type (WT) or Trpv1-TG naive (CD4+CD45RBhiCD25–) T cells or a mixture of 3 × 105 WT naive CD4+ T cells plus 1.5 × 105 WT Treg (CD4+CD45RBloCD25+) cells (WT naive T cells + Treg). (b) Disease activity index (DAI) of the mice in a. (c) Microcopy of colon sections from the mice in a, stained with hematoxylin and eosin. Scale bar, 1 mm (main images; 20× objective) or 100 μm (insets; 1× objective). (d) Colitis scores of the mice in a. (e) Cytokine concentrations in colonic explants from the mice in a after 24 h of culture. (f) Cytokine production by splenic or (g) MLN CD4+ T cells isolated from the mice in a and restimulated for 24 h with anti-CD3 (10 μg/ml plate-bound) plus anti-CD28 (1 μg/ml soluble). *P < 0.05, **P < 0.01 and ***P < 0.001 (one-way (b,d–g) or two-way (a) ANOVA with post-hoc Bonferroni's test). Data are from one experiment representative of two experiments (mean ± s.e.m. (n = 5–6 mice per group)).
Supplementary Figure 10 Proposed model for the regulation of T cell activation by TRPV1.
TCR stimulation induces the activation of protein tyrosine kinases, such as Lck, which initiate a cascade of phosphorylation events. Our data indicate that TRPV1 is part of this signaling cascade and that tyrosine phosphorylation by Lck is likely the gating mechanism of TRPV1 after TCR stimulation. In addition to CRAC, Voltage-gated Ca2+ channels (CaV) and other TRPs channels, we identified that TRPV1 is required for the proper transduction of TCR induced-Ca2+ influx, TCR-mediated signaling events (for example, MAPKs, NFAT-1 and NF-κB), and downstream activation and acquisition of proinflammatory properties by CD4+ T cells.
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Bertin, S., Aoki-Nonaka, Y., de Jong, P. et al. The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4+ T cells. Nat Immunol 15, 1055–1063 (2014). https://doi.org/10.1038/ni.3009
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DOI: https://doi.org/10.1038/ni.3009
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