Sunday, October 1, 2023
|
ITP |
Controls |
|
|---|---|---|
| Number of samples | 83 | 51 |
| Age, y | ||
| Median | 45 | 54 |
| IQR | 22–86 | 23–87 |
| Platelet count | ||
| Median | 37 | N/A |
| IQR | 7–249 | |
| Sex ratio (male:female) | 1.2:1 | 1:1 |
| Longitudinal samples | 24 | N/A |
Table 1. Cohort characteristics
IQR, interquartile range; N/A, not achieved.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for hematologists, oncologists, immunologists, internists, and other clinicians who treat and manage patients with immune thrombocytopenia.
The goal of this activity is for learners to be better able to describe the role of cytotoxic CD8+ T cell clones and mechanisms of CD8+ T-cell-mediated platelet destruction in patients with immune thrombocytopenia, based on a multidimensional approach comparing patients with immune thrombocytopenia with age-matched controls, using immunophenotyping, next-generation sequencing of T cell receptor genes, single-cell RNA sequencing, and functional T cell and platelet assays.
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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.
Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by thrombocytopenia with increased morbidity and mortality due to bleeding, fatigue, and treatment-related complications.[1–4] International guidelines highlight a lack of diagnostic and prognostic markers, limited data to guide treatment decisions, and heterogeneity of responses to treatment.[2,5,6]
The initial biological studies in ITP focused on the role of autoantibodies, with passive transfer experiments demonstrating a pathogenic role for autoantibodies against platelet surface antigens.[7–9] Drug discovery efforts have therefore focused on the suppression of aberrant humoral immunity via B-cell depletion (by targeting CD20 or B-cell activating factor),[10,11] immunoreceptor signaling disruption (by blocking spleen tyrosine kinase[12] or Bruton tyrosine kinase),[13] and autoantibody activity inhibition (by using steroids, IV immunoglobulin, or neonatal Fc receptor inhibition).[14]
Nonetheless, antibody-independent regulators of thrombocytopenia such as T cells are likely to play an important role in ITP because antiplatelet antibodies are difficult to detect in many patients;[15] antiplatelet antibodies do not predict response to treatment;[16] B-cell–directed therapies are not effective in many patients;[17] and a proportion of patients remain refractory to all existing therapies, which suggests other mechanisms of disease. Although abnormalities in CD4+ T cells that are skewed toward Th1[18–20] and abnormal number and function of T regulatory cells (Tregs)[20] are thought to drive the autoimmune process, the role of CD8+ T cells remains unclear.
Cytotoxic CD8+ T cells were first implicated in ITP in 2003,[21] and, subsequently, data from murine models of ITP have suggested that CD8+ T cells contribute to thrombocytopenia in vivo.[22,23] However, the nature or importance of CD8+ T cells in patients with ITP is not known, and the role of platelet-specific CD8+ T cells have not been characterized in humans.[24–28]
We therefore pursued several orthogonal approaches to identify CD8+ T-cell clones and explore CD8+ T-cell–mediated platelet destruction in patients with ITP.
