Malik, Amna;
Sayed, Anwar A;
Han, Panpan;
Tan, Michelle MH;
Watt, Eleanor;
Constantinescu-Bercu, Adela;
Cocker, Alexander TH;
... Cooper, Nichola; + view all
(2023)
The role of CD8+ T cell clones in immune thrombocytopenia.
Blood
10.1182/blood.2022018380.
(In press).
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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 multi-dimensional approach to explore the role of cytotoxic CD8+ T cells in ITP. We characterised patients with ITP and compared them to 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-g, tumour necrosis factor-a, 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 T cell receptor 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-g and trigger platelet activation and apoptosis through 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.
| Type: | Article |
|---|---|
| Title: | The role of CD8+ T cell clones in immune thrombocytopenia |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1182/blood.2022018380 |
| Publisher version: | https://doi.org/10.1182/blood.2022018380 |
| Language: | English |
| Additional information: | Copyright © 2023 American Society of Hematology Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10164885 |
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