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

Author(s): Amna Malik1;Anwar A. Sayed1,2;Panpan Han3,4;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-Crawley1,8;James B. Bussel9;James L. Zehnder3;Stuart Adams5;Bing M. Zhang3;Nichola Cooper1
Source: Blood (2023) 141 (20): 2417–2429
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

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


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.


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

Leave a Comment

Your email address will not be published. Required fields are marked *

Related Articles

Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS)

This great Italian study uses eltrombopag in patients with low/intermediate risk MDS. The intervention arm had significantly fewer minor bleeding events and better platelet counts that were durable. Those with higher baseline Hb’s seemed to respond better to therapy, particularly if the Hb was >8g/dL. AML evolution/blast progression was not more common in the treatment arm, which refutes some prior concerns.

Read More »

Introduction to a How I Treat series on management of high-risk patients following allogeneic transplant

Interesting prospective study assessing outcomes in ITP in pregnant women while measuring neonatal ITP in the developing child, with a control of non-pregnant women for comparison. Pregnancy-ITP was associated with a 2.7x higher rate of recurrent disease. However, bleeding was similar in pregnant vs. non-pregnant women. NITP risk was associated with more severe ITP disease in the mother and the severity of the disease, as well as prior h/o ITP in the mother.

Read More »

Efficacy and Safety of Intravenous Efgartigimod in Adults with Primary Immune Thrombocytopenia: Results of a Phase 3, Multicenter, Double-Blinded, Placebo-Controlled, Randomized Clinical Trial (ADVANCE IV)

Another new (potential) option for refractory ITP patients, efgartigimod is an IgG1-Fc-fragment engineered to reduce IgG autoantibody levels.  131 patients enrolled and 67% had >=3 prior lines of therapy, placebo controlled study.  The study group had a 90% sustained platelet response, with >50% having plt counts of >30k >= 7 days apart.

Read More »