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

被引:38
作者
Malik, Amna [1 ]
Sayed, Anwar A. [1 ,2 ]
Han, Panpan [3 ,4 ]
Tan, Michelle M. H. [1 ]
Watt, Eleanor [5 ]
Constantinescu-Bercu, Adela [1 ]
Cocker, Alexander T. H. [6 ]
Khoder, Ahmad [1 ]
Saputil, Rocel C. [1 ]
Thorley, Emma [1 ]
Teklemichael, Ariam [1 ]
Ding, Yunchuan [1 ]
Hart, Alice C. J. [1 ]
Zhang, Haiyu [3 ]
Mitchell, Wayne A. [7 ]
Imami, Nesrina [6 ]
Crawley, James T. B. [1 ]
Salles-Crawely, Isabelle I. [1 ,8 ]
Bussel, James B. [9 ]
Zehnder, James L. [3 ]
Adams, Stuart [5 ]
Zhang, Bing M. [1 ,3 ,11 ]
Cooper, Nichola [1 ,10 ]
机构
[1] Imperial Coll London, Ctr Haematol, Dept Immunol & flammat, London, England
[2] Taibah Univ, Dept Med Microbiol & Immunol, Medina, Saudi Arabia
[3] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA USA
[4] Shandong First Med Univ, Shandong Prov Hosp, Dept Hematol, Jinan, Peoples R China
[5] Great Ormond St Hosp Sick Children, Specialist Integrated Haematol & Malignancy Diagno, London, England
[6] Imperial Coll London, Ctr Immunol & Vaccinol, London, England
[7] Imperial Coll London, Dept Immunol & flammat, London, England
[8] Univ London, Mol & Clin Sci Res Inst, Vasc Biol Res Ctr, St Georges, London, England
[9] Weill Cornell Med, Dept Pediat, New York, NY USA
[10] Imperial Coll London, Hammersmith Hosp, Ctr Haematol, Dept Haematol, London W12 OHS, England
[11] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA
基金
美国国家卫生研究院;
关键词
CLASS-I MOLECULES; MEDIATED CYTOTOXICITY; PRESENT ANTIGEN; PLATELETS; PURPURA; PHENOTYPE; RESPONSES; CONSENSUS;
D O I
10.1182/blood.2022018380
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 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 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.
引用
收藏
页码:2417 / 2429
页数:13
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