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Deep phenotyping detects a pathological CD4+ T-cell complosome signature in systemic sclerosis

Cellular & Molecular Immunology volume 17, pages 1010–1013 (2020)Cite this article

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CD4+ T-helper 1 cell (Th1) function is closely regulated by an intrinsic developmental program in which activation/induction and proinflammatory interferon (IFN)-γ secretion are followed by a deactivation/contraction period characterized by a switch into cosecretion of immunoregulatory interleukin (IL)-10. Autocrine intracellular complement (complosome) activity plays a vital role in Th1 initiation and contraction: T-cell receptor (TCR) stimulation induces intracellular activation of the key complement components C3 (through cathepsin L (CTSL) cleavage) and C5, which leads to intrinsic engagement of CD46 by C3b, of the C3a receptor (C3aR) by C3a, and of the C5a receptors (C5aR1 and C5aR2) by C5a.1,2 These events mediate the metabolic programming required for IFN-γ production and Th1 induction.3 CD46-mediated signals also support subsequent IL-10 switching and Th1 contraction by increasing the oxidative phosphorylation to glycolysis ratio, while autocrine C5aR2 engagement by secreted des-arginated C5a (C5a-desArg) suppresses intracellular C5aR1 activity (Supplementary Fig. 1a depicts a model summarizing the role of the complosome in Th1 induction and contraction).

Diminished or augmented complosome activation and function are associated with recurrent infections or hyperactive Th1 responses in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), respectively.4 This raises the possibility that T-cell complosome dysregulation may operate in other immune-mediated rheumatic diseases, such as systemic sclerosis (scleroderma, SSc).5 Designated as an orphan disease with a high unmet medical need, SSc is characterized by autoimmunity, vasculopathy and progressive fibrotic changes to major internal organs.6 Hyperactive T-helper cells, often of the Th2 subtype, and increases in IL-6- and/or IL-17-producing CD4+ T cells in the blood and skin of patients have been described conclusively.7,8 However, the evidence for distinct Th1 involvement is less clear, as some researchers have noted augmented Th1 activity, while others have failed to observe this. A method to comprehensively and rapidly monitor complosome activity in cells, however, is currently unavailable: traditional FACS-based assays generally do not permit measurement of sufficient markers to assess complosome activity and cellular effector function at a single-cell level. Similarly, RNA-seq and gene array analyses fail to inform on the intracellular or extracellular localization of complement components and on their protein activation states. Here, we addressed this need for advanced complosome/complement technologies and generated the first complement-compatible antibody panel suitable for analyzing the complosome signature of cells comprehensively by mass cytometry (MC, CyTOF®) technology. We further utilized this novel MC complosome panel to evaluate CD4+ T cells isolated from a well-characterized cohort of early-stage treatment-naïve diffuse cutaneous systemic sclerosis (dcSSc) patients for complosome perturbations. This strategy focused on the detection of dysregulation in Th1 induction or contraction in SSc, and our results indicate potential biological coupling of dysregulated complosome activity in a broader range of immune-mediated rheumatic disease states.

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Fig. 1: T cells from patients with diffuse cutaneous scleroderma have reduced capacity for Th1 contraction and a distinct complosome signature.

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Acknowledgements

We thank the patients and the healthy donors for their support. This work was financed by MRC Centre grant MR/J006742/1, an EU-funded Innovative Medicines Initiative BTCURE (C.K.), a Wellcome Trust Investigator Award (C.K.), the King’s Bioscience Institute at King’s College London (G.A.), The King’ College London BRC Genomics Facility, the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, National Institute Of Health grant R21 AI123789 (D.E.H.) and by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH (C.K.). D.E.H. and L.M. are grateful for the support of the Washington University School of Medicine Immunomonitoring Laboratory. V.H.O., C.P.D. and D.A. are grateful for funding support from Versus Arthritis, Scleroderma & Raynaud’s UK, Rosetrees Trust and Royal Free Charity. T.M.W. is supported by a National Health and Medical Research Council Fellowship (1105420). SK is supported by Cancer Research UK (CRUK).  The authors acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Center awarded to Guy’s & St Thomas’ NHS Foundation Trust in Partnership with King’s College London and King’s College Hospital NHS Foundation Trust.

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Author notes

  1. These authors contributed equally: Giuseppina Arbore, Voon H. Ong

  2. These authors jointly supervised this work: Shahram Kordasti, Claudia Kemper, Dennis E. Hourcade

Authors and Affiliations

  1. Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milano, Italy

    Giuseppina Arbore

  2. Centre for Rheumatology and Connective Tissue Diseases, UCL Division of Medicine, London, UK

    Voon H. Ong, Christopher P. Denton & David Abraham

  3. Systems Cancer Immunology Lab, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK

    Benedetta Costantini, Kevin Blighe, Paola Nocerino & Shahram Kordasti

  4. Complement and Inflammation Research Section, NIH, NHLBI, Bethesda, MD, USA

    Leo Placais & Claudia Kemper

  5. Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA

    Lynne Mitchell & Dennis E. Hourcade

  6. School of Immunology and Microbial Sciences, King’s College London, London, UK

    Richard Ellis, Susanne Heck & Claudia Kemper

  7. School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, Australia

    Trent M. Woodruff

  8. Haematology Department, Guy’s Hospital, London, UK

    Shahram Kordasti

  9. Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany

    Claudia Kemper

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  1. Giuseppina Arbore
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Contributions

D.E.H, C.K. and S.K. conceived and directed the study, performed experiments and wrote the manuscript. G.A., B.C., L.P., T.M.W. and C.K. designed, performed and/or analyzed the T-cell activation and ‘rescue’ experiments. L.M., R.E., S.H., S.K., K.B. and P.N., generated and validated the heavy metal-conjugated CyTOF® compatible antibody panel and/or performed and/or analyzed the CyTOF experiments. V.H.O., D.A., and C.P.D. designed and analyzed the experiments and data derived from cells isolated from the patients. All authors discussed and edited the manuscript. G.A. and V.H.O. contributed equally to the work and are shared first authors.

Corresponding authors

Correspondence to Shahram Kordasti, Claudia Kemper or Dennis E. Hourcade.

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Competing interests

T.M.W. is a co-inventor on a patent for C5aR2 agonists as immunomodulators for inflammatory disease. The authors have no additional financial interests.

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Arbore, G., Ong, V.H., Costantini, B. et al. Deep phenotyping detects a pathological CD4+ T-cell complosome signature in systemic sclerosis. Cell Mol Immunol 17, 1010–1013 (2020). https://doi.org/10.1038/s41423-019-0360-8

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