Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance.

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Presentation transcript:

Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses Moira Paroni, PhD, Virginia Maltese, MD, Marco De Simone, PhD, Valeria Ranzani, PhD, Paola Larghi, PhD, Chiara Fenoglio, PhD, Anna M. Pietroboni, MD, Milena A. De Riz, PhD, Maria C. Crosti, BSc, Stefano Maglie, BSc, Monica Moro, PhD, Flavio Caprioli, PhD, Riccardo Rossi, PhD, Grazisa Rossetti, PhD, Daniela Galimberti, PhD, Massimiliano Pagani, PhD, Elio Scarpini, MD, Sergio Abrignani, PhD, Jens Geginat, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 3, Pages 797-808 (September 2017) DOI: 10.1016/j.jaci.2016.11.045 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 TH1/TH17CM cells are closely related to conventional TH17 cells but produce high amounts of proinflammatory cytokines. A, Gating strategy to identify TH1, TH17, and TH1/TH17 cell subsets among antigen-experienced helper T cells according to chemokine receptor expression. B, CCR7 expression on gated CCR5+ and CCR5− memory T cells. One representative donor of 4 is shown. C, Production of IFN-γ, IL-17, GM-CSF, and IL-22 of the indicated T-cell subsets was measured in ex vivo–stimulated purified T-cell subsets by means of intracellular staining (n = 10-19; 1-way ANOVA). D, Heat map and hierarchical clustering of 242 differentially expressed genes in TH17, TH1CM, TH1EM, TH1/TH17CM, and TH1/TH17EM cell subsets from at least 3 different donors. E, Box plots of CCR6 expression on TH1CM cells and CXCR3 expression on TH17 cells on in vitro anti-CD3/CD28 stimulation in the absence of exogenous cytokines (white box) and under TH1 (dark gray box) or TH17 (gray box) conditions. In addition, box plots of the percentage of IFN-γ– and IL-17–coproducing T cells under the same conditions are shown (n = 4-6; 1-way ANOVA). *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Levels of TH1/TH17CM cells and cytokines are selectively increased in patients with RR-MS with severe disease. A, Intracellular expression of cytokines in CD4+ T cells from peripheral blood in patients with different types of MS (ie, patients with RR-MS with MSSS < 1 [RR < 1, n = 6] or MSSS > 1 [RR > 1, n = 6] and patients with progressive MS [PR; n = 7]) compared with age- and sex-matched HDs (n = 20). Dot plots show intracellular IL-17 versus IFN-γ or GM-CSF versus IL-22 staining in gated CD4+ T cells after brief polyclonal stimulation in representative subjects ex vivo. Box plots show quantitative flow cytometric analysis of percentages of CD4+ T cells that produce IFN-γ and IL-17 alone or in combination (upper panel) or GM-CSF or IL-22 (lower panel; 1-way ANOVA). B, Frequencies of TH1CM, TH1EM, TH1/TH17CM, TH1/TH17EM, and TH17 cell subsets in HDs (n = 20) and different cohorts of patients with MS (RR < 1, n = 6; RR > 1, n = 8; PR, n = 10), as indicated. Statistical significance was calculated by using 1-way ANOVA between patients with MS and HDs and among different subtypes of MS. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TH1/TH17CM cells in patients with MS become highly autoreactive but lose responsiveness to JCV. A, Autoreactive proliferation of the indicated helper T-cell subsets with autologous CD1c+ DCs in the absence of exogenous antigens in HDs (n = 6, white boxes) and patients with RR-MS (n = 6-8, gray boxes). Shown are box plots of divided cells after 5 days and statistical significances (unpaired t test for the comparison of the same subset in HDs vs patients with RR-MS and 1-way ANOVA to compare different T-cell subsets in the same cohort). B, Antigen-specific proliferation of the indicated helper T cells with autologous CD14+ monocytes in HDs (n = 6) and patients with MS (n = 5-9) in the presence of myelin peptides (MOG/MBP, left graph), JCV (VP1), or a mix of immune-dominant EBV-derived peptides (middle and right graphs, respectively). Shown are box plots of divided cells after 7 days induced by specific peptides and statistical significances (analysis as in Fig 3, A). *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Autoreactive TH1/TH17 cells and virus-specific TH1 cells are enriched in the CSF of patients with active MS. A, Chemokines in the CSF of patients with MS shortly after an attack (n = 9) and control subjects without MS (n = 5) were quantified by means of ELISA and represented by using box plots (unpaired t test). B, Frequencies of TH1, TH1/TH17, and TH17 cell subsets among helper T cells in the CSF of patients with MS (n = 10). C, Mean percentage of CD40L+, IFN-γ+, and CD40L+IFN-γ+ cells among CSF-derived TH1, TH1/TH17, and TH17 cell lines in response to autologous CD14+ monocytes in the absence of exogenous antigens were measured to assess autoreactivity (n = 5). D, Mean percentages of CD40L+, IFN-γ+, and CD40L+IFN-γ+ cells induced by antigenic myelin-derived (MOG and MBP, left graph), JCV-derived, or EBV-derived peptides (middle and right graphs, respectively; n = 5). CD40L+/IFN-γ+ cells induced by monocytes alone were subtracted. In Fig 4, C and D, statistical significance was calculated by using 1-way ANOVA on total percentages of responding cells. *P < .05 and **P < .005. Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Efficient but unselective targeting of TH1/TH17CM cells by fingolimod and natalizumab therapies. A, Box plots of total CD4+ T cells among lymphocytes in peripheral blood of fingolimod-treated (n = 13) or natalizumab-treated (n = 8) and untreated control patients with RR-MS (n = 14; 1-way ANOVA). B, Box plots of TH1, TH1/TH17, and TH17 cell subsets in natalizumab-treated (n = 8) and untreated (n = 14) patients with RR-MS (unpaired t test for the comparison of the same subset in untreated versus treated patients, 1-way ANOVA to compare different T-cell subsets in the same cohort). C, Box plots of α4/β1-integrin expression on circulating TH1 and TH1/TH17 cell subsets and TH17 cells (n = 7, 1-way ANOVA). D, Fold reduction of TH1, TH1/TH17, and TH17 cell subsets in fingolimod-treated patients (n = 13) related to control untreated (n = 14) patients with RR-MS. *P < .05, **P < .005, and ***P < .0005. Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2017 140, 797-808DOI: (10.1016/j.jaci.2016.11.045) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions