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

The role of CD8+ T cell clones in immune thrombocytopenia. Blood Malik, A., Sayed, A. A., Han, P., Tan, M. M., Watt, E., Constantinescu-Bercu, A., Cocker, A. T., Khoder, A., Saputil, R. C., Thorley, E. V., Teklemichael, A., Ding, Y., Hart, A. C., Zhang, H., Mitchell, W. A., Imami, N., Crawley, J. T., Salles-Crawley, I. I., Bussel, J. B., Zehnder, J. L., Adams, S. P., Zhang, B. M., Cooper, N. 2023

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.

View details for DOI 10.1182/blood.2022018380

View details for PubMedID 36749920