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

Author(s): Amna Malik¹;Anwar A. Sayed^1,2;Panpan Han^3,4;Michelle M. H. Tan¹;Eleanor Watt⁵;Adela Constantinescu-Bercu¹;Alexander T. H. Cocker⁶;Ahmad Khoder¹;Rocel C. Saputil¹;Emma Thorley¹;Ariam Teklemichael¹;Yunchuan Ding¹;Alice C. J. Hart¹;Haiyu Zhang³;Wayne A. Mitchell⁷;Nesrina Imami⁶;James T. B. Crawley¹;Isabelle I. Salles-Crawley^1,8;James B. Bussel⁹;James L. Zehnder³;Stuart Adams⁵;Bing M. Zhang³;Nichola Cooper¹

Source: Blood (2023) 141 (20): 2417–2429

Dr. Anjan Patel's Thoughts

Thought provoking article regarding a non-antibody mediated mechanism in chronic ITP.

KEY POINTS

Patients with chronic ITP had clonal expansions of disease-associated TEMRA CD8+ T cells. CD8+ T cells bind to platelets and cause their activation and apoptosis, defining an antibody-independent mechanism of platelet destruction.

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.

Author Affiliations

¹Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom;²Department of Medical Microbiology and Immunology, Taibah University, Medina, Saudi Arabia;³Department of Pathology, Stanford University School of Medicine, Stanford, CA;⁴Department of Hematology, Shandong Province Hospital, Shandong First Medical University, Jinan, China;⁵Specialist Integrated Haematology and Malignancy Diagnostic Service–Haematology, Great Ormond Street Hospital for Children, London, United Kingdom;⁶Centre for Immunology and Vaccinology, Imperial College London, London, United Kingdom;⁷Department of Immunology and Inflammation, Imperial College London, London, United Kingdom;⁸Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St. George’s, University of London, London, United Kingdom;⁹Department of Pediatrics, Weill Cornell Medicine, New York, NY

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