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Table 1.  

ITP

Controls

Number of samples 83 51
Age, y
   Median 45 54
   IQR 22–86 23–87
Platelet count
   Median 37 N/A
   IQR 7–249
Sex ratio (male:female) 1.2:1 1:1
Longitudinal samples 24 N/A

Table 1. Cohort characteristics

IQR, interquartile range; N/A, not achieved.

CME / ABIM MOC

The role of CD8+ T-cell clones in immune thrombocytopenia

  • Authors: Amna Malik, PhD; Anwar A. Sayed, PhD, MBBS, MSc; Panpan Han, PhD; Michelle M.H. Tan, MSc; Eleanor Watt, BSc; Adela Constantinescu-Bercu, PhD; Alexander T.H. Cocker, PhD; Ahmad Khoder, MD, PhD, MRCP, ASCP; Rocel Christine Saputil, BSc, MSc; Emma V. Thorley, MB BChir, BA; Ariam Teklemichael, BSc; Yunchuan Ding, PhD; Alice C.J. Hart, MBBS, BSc, MRCP, FRCPath; Haiyu Zhang, PhD; Wayne A. Mitchell, PhD; Nesrina Imami, PhD; James T.B. Crawley, PhD; Isabelle I. Salles-Crawley, PhD; James B. Bussel, MD; James L. Zehnder, MD; Stuart Paul Adams, PhD; Bing M. Zhang, MD, MS; Nichola Cooper, FRCP FRCPath MD
  • CME / ABIM MOC Released: 5/18/2023
  • Valid for credit through: 5/18/2024
Start Activity

  • Credits Available

    Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 1.00 ABIM MOC points

    You Are Eligible For

    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for hematologists, oncologists, immunologists, internists, and other clinicians who treat and manage patients with immune thrombocytopenia.

The goal of this activity is for learners to be better able to describe the role of cytotoxic CD8+ T cell clones and mechanisms of CD8+ T-cell-mediated platelet destruction in patients with immune thrombocytopenia, based on a multidimensional approach comparing patients with immune thrombocytopenia with age-matched controls, using immunophenotyping, next-generation sequencing of T cell receptor genes, single-cell RNA sequencing, and functional T cell and platelet assays.

Upon completion of this activity, participants will:

  1. Assess the role of cytotoxic CD8+ T-cell clones in patients with immune thrombocytopenia, based on a multidimensional approach comparing patients with immune thrombocytopenia with age-matched controls
  2. Evaluate the mechanisms of CD8+ T-cell-mediated platelet destruction in patients with immune thrombocytopenia, based on a multidimensional approach comparing patients with immune thrombocytopenia with age-matched controls
  3. Determine the clinical and research implications of the role of cytotoxic CD8+ T-cell clones and mechanisms of CD8+ T-cell-mediated platelet destruction in patients with immune thrombocytopenia


Disclosures

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All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Amna Malik, PhD

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Anwar A. Sayed, PhD, MBBS, MSc

    Department of Medical Microbiology and Immunology
    Taibah University
    Medina, Saudi Arabia and
    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Panpan Han, PhD

    Department of Hematology
    Shandong Province Hospital
    Shandong First Medical University
    Jinan, China

  • Michelle M.H. Tan, MSc

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Eleanor Watt, BSc

    Great Ormond Street Hospital for Children
    London, United Kingdom

  • Adela Constantinescu-Bercu, PhD

    University College London
    London, United Kingdom

  • Alexander T.H. Cocker, PhD

    Imperial College
    London, United Kingdom

  • Ahmad Khoder, MD, PhD, MRCP, ASCP

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Rocel Christine Saputil, BSc, MSc

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Emma V. Thorley, MB BChir, BA

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Ariam Teklemichael, BSc

    Department of Haematology
    Hammersmith Hospital
    Imperial Health Care NHS Trust
    London, United Kingdom

  • Yunchuan Ding, PhD

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Alice C.J. Hart, MBBS, BSc, MRCP, FRCPath

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Haiyu Zhang, PhD

    Stanford University
    Stanford, United States

  • Wayne A. Mitchell, PhD

    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • Nesrina Imami, PhD

    Imperial College London
    London, United Kingdom

  • James T.B. Crawley, PhD

    Imperial College London
    London, United Kingdom

  • Isabelle I. Salles-Crawley, PhD

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

  • James B. Bussel, MD

    Department of Pediatrics
    Division of Hematology/Oncology
    Weill Cornell Medicine
    New York, New York

  • James L. Zehnder, MD

    Stanford University
    Stanford, California

  • Stuart Paul Adams, PhD

    Haematology
    Great Ormond Street Hospital for Children
    London, United Kingdom

  • Bing M. Zhang, MD, MS

    Stanford University
    Stanford, California

  • Nichola Cooper, FRCP FRCPath, MD

    Centre for Haematology
    Department of Immunology and Inflammation
    Imperial College London
    London, United Kingdom

CME Author

  • Laurie Barclay, MD

    Freelance writer and reviewer
    Medscape, LLC

    Disclosures

    Laurie Barclay, MD has no relevant financial relationships.

Editor

  • Jorge Di Paola, MD

    Associate Editor, Blood

Compliance Reviewer

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.


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    For Physicians

  • Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

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From Blood
CME / ABIM MOC

The role of CD8+ T-cell clones in immune thrombocytopenia

Authors: Amna Malik, PhD; Anwar A. Sayed, PhD, MBBS, MSc; Panpan Han, PhD; Michelle M.H. Tan, MSc; Eleanor Watt, BSc; Adela Constantinescu-Bercu, PhD; Alexander T.H. Cocker, PhD; Ahmad Khoder, MD, PhD, MRCP, ASCP; Rocel Christine Saputil, BSc, MSc; Emma V. Thorley, MB BChir, BA; Ariam Teklemichael, BSc; Yunchuan Ding, PhD; Alice C.J. Hart, MBBS, BSc, MRCP, FRCPath; Haiyu Zhang, PhD; Wayne A. Mitchell, PhD; Nesrina Imami, PhD; James T.B. Crawley, PhD; Isabelle I. Salles-Crawley, PhD; James B. Bussel, MD; James L. Zehnder, MD; Stuart Paul Adams, PhD; Bing M. Zhang, MD, MS; Nichola Cooper, FRCP FRCPath MDFaculty and Disclosures

CME / ABIM MOC Released: 5/18/2023

Valid for credit through: 5/18/2024

processing....

Abstract and Introduction

Abstract

Immune thrombocytopenia (ITP) is traditionally considered an antibody-mediated disease. However, a number of features suggest alternative mechanisms of platelet destruction. In this study, we use a multidimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterized patients with ITP and compared them with age-matched controls using immunophenotyping, next-generation sequencing of T-cell receptor (TCR) genes, single-cell RNA sequencing, and functional T-cell and platelet assays. We found that adults with chronic ITP have increased polyfunctional, terminally differentiated effector memory CD8+ T cells (CD45RA+CD62L) expressing intracellular interferon gamma, tumor necrosis factor α, and granzyme B, defining them as TEMRA cells. These TEMRA cells expand when the platelet count falls and show no evidence of physiological exhaustion. Deep sequencing of the TCR showed expanded T-cell clones in patients with ITP. T-cell clones persisted over many years, were more prominent in patients with refractory disease, and expanded when the platelet count was low. Combined single-cell RNA and TCR sequencing of CD8+ T cells confirmed that the expanded clones are TEMRA cells. Using in vitro model systems, we show that CD8+ T cells from patients with ITP form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the TCR-mediated release of cytotoxic granules. These findings of clonally expanded CD8+ T cells causing platelet activation and apoptosis provide an antibody-independent mechanism of platelet destruction, indicating that targeting specific T-cell clones could be a novel therapeutic approach for patients with refractory ITP.

Introduction

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by thrombocytopenia with increased morbidity and mortality due to bleeding, fatigue, and treatment-related complications.[1–4] International guidelines highlight a lack of diagnostic and prognostic markers, limited data to guide treatment decisions, and heterogeneity of responses to treatment.[2,5,6]

The initial biological studies in ITP focused on the role of autoantibodies, with passive transfer experiments demonstrating a pathogenic role for autoantibodies against platelet surface antigens.[7–9] Drug discovery efforts have therefore focused on the suppression of aberrant humoral immunity via B-cell depletion (by targeting CD20 or B-cell activating factor),[10,11] immunoreceptor signaling disruption (by blocking spleen tyrosine kinase[12] or Bruton tyrosine kinase),[13] and autoantibody activity inhibition (by using steroids, IV immunoglobulin, or neonatal Fc receptor inhibition).[14]

Nonetheless, antibody-independent regulators of thrombocytopenia such as T cells are likely to play an important role in ITP because antiplatelet antibodies are difficult to detect in many patients;[15] antiplatelet antibodies do not predict response to treatment;[16] B-cell–directed therapies are not effective in many patients;[17] and a proportion of patients remain refractory to all existing therapies, which suggests other mechanisms of disease. Although abnormalities in CD4+ T cells that are skewed toward Th1[18–20] and abnormal number and function of T regulatory cells (Tregs)[20] are thought to drive the autoimmune process, the role of CD8+ T cells remains unclear.

Cytotoxic CD8+ T cells were first implicated in ITP in 2003,[21] and, subsequently, data from murine models of ITP have suggested that CD8+ T cells contribute to thrombocytopenia in vivo.[22,23] However, the nature or importance of CD8+ T cells in patients with ITP is not known, and the role of platelet-specific CD8+ T cells have not been characterized in humans.[24–28]

We therefore pursued several orthogonal approaches to identify CD8+ T-cell clones and explore CD8+ T-cell–mediated platelet destruction in patients with ITP.