The role of CD8+ T cell clones in immune thrombocytopenia

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.

Maintenence rituximab following induction in autoimmune cytopenias

“…In one study of high-dose dexamethasone with rituximab, half the relapsed patients had VbetaTCR clones compared to only one patient in lasting remission. 26 Studies by Stasi et al related response to rituximab to absence of abnormal Tcell populations. 27,28 Addition of an anti-T-cell agent, either MMF as used by one patient, or another agent, might also be appropriate.…”

Pathogenesis of refractory ITP: Overview

“…11,[50][51][52][53][54][55] In one study, reduction in T-cell receptor diversity was noted in patients followed longitudinally. 56 In addition to potentially serving as a biomarker of more severe disease, clonality may provide insight into the immunoregulatory pathways that contribute to drug resistance. Larger prospective studies are needed to determine whether clonal populations are detectable at initial presentation and/or evolve over time leading to rITP.…”

The role of genetics in refractory immune thrombocytopenia

“…A recent study showed that expanded T‐cell clones are more frequent in patients with rITP (patients with ITP more than 12 months duration and refractory to at least two prior treatment) 8 . Recent evidence suggests that these CD8 T‐cell clones can directly kill platelets by TCR engaging with MHC class I on the platelets, resulting in the release of granzyme and perforin by CD8 T cells, resulting in annexin V and P selectin exposure on platelets, indicating a direct role in killing 9 (Figure 1). The relevant contribution of CD8 T cells to thrombocytopenia needs further understanding.…”

“…Activated CD8 T cell TEMRA clones interact with platelets through TCR‐MHC class 1, resulting in the release of perforin and granzyme and the activation and apoptosis of platelets. Source : Blood 2023 9 .…”