Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia

Huuhtanen, Jani; Bhattacharya, Dipabarna; Lönnberg, Tapio; Kankainen, Matti; Kerr, Cassandra M; Theodoropoulos, Jason; Rajala, Hanna; Gurnari, Carmelo; Kasanen, Tiina; Braun, Till; Teramo, Antonella; Zambello, Renato; Herling, Marco; Ishida, Fumihiro; Kawakami, Toru; Salmi, Teea; Loughran, Thomas P.; Maciejewski, Jaroslaw P.; Lähdesmäki, Harri; Kelkka, Tiina; Mustjoki, Satu

doi:10.1038/s41467-022-29173-z

Cited by 35 publications

(32 citation statements)

References 69 publications

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“…Rather, these “neoplastic” T-LGLs may represent an exaggerated T cell response that have escaped normal homeostatic control. To date, few studies investigating the T-LGL TCR repertoire using high-throughput methods such as next generation sequencing have been performed ( 22 , 56 , 57 ). In this study, we did not assess T cell clonality, however, continuing efforts are underway to characterize the TCR sequences of T-LGLs in IBM using these in-depth sequencing technologies.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, the utility of this threshold has been debated, with several studies defining T-LGLL using lower cell counts (>0.5x10 9 /L of blood), when appropriate clinical criteria were met ( 16 – 18 , 21 ). Furthermore, the classification of T-LGLL as a neoplastic disease is often debated, and despite its reported monoclonal nature, T-LGLL is rarely aggressive like other lymphoproliferative diseases ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

et al. 2023

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IntroductionInclusion body myositis (IBM) is a progressive inflammatory myopathy characterised by skeletal muscle infiltration and myofibre invasion by CD8+ T lymphocytes. In some cases, IBM has been reported to be associated with a systemic lymphoproliferative disorder of CD8+ T cells exhibiting a highly differentiated effector phenotype known as T cell Large Granular Lymphocytic Leukemia (T-LGLL). MethodsWe investigated the incidence of a CD8+ T-LGL lymphoproliferative disorder in 85 IBM patients and an aged-matched group of 56 Healthy Controls (HC). Further, we analysed the phenotypical characteristics of the expanded T-LGLs and investigated whether their occurrence was associated with any particular HLA alleles or clinical characteristics. ResultsBlood cell analysis by flow cytometry revealed expansion of T-LGLs in 34 of the 85 (40%) IBM patients. The T cell immunophenotype of T-LGLHIGH patients was characterised by increased expression of surface molecules including CD57 and KLRG1, and to a lesser extent of CD94 and CD56 predominantly in CD8+ T cells, although we also observed modest changes in CD4+ T cells and γδ T cells. Analysis of Ki67 in CD57+ KLRG1+ T cells revealed that only a small proportion of these cells was proliferating. Comparative analysis of CD8+ and CD4+ T cells isolated from matched blood and muscle samples donated by three patients indicated a consistent pattern of more pronounced alterations in muscles, although not significant due to small sample size. In the T-LGLHIGH patient group, we found increased frequencies of perforin-producing CD8+ and CD4+ T cells that were moderately correlated to combined CD57 and KLRG1 expression. Investigation of the HLA haplotypes of 75 IBM patients identified that carriage of the HLA-C*14:02:01 allele was significantly higher in T-LGLHIGH compared to T-LGLLOW individuals. Expansion of T-LGL was not significantly associated with seropositivity patient status for anti-cytosolic 5'-nucleotidase 1A autoantibodies. Clinically, the age at disease onset and disease duration were similar in the T-LGLHIGH and T-LGLLOW patient groups. However, metadata analysis of functional alterations indicated that patients with expanded T-LGL more frequently relied on mobility aids than T-LGLLOW patients indicating greater disease severity. ConclusionAltogether, these results suggest that T-LGL expansion occurring in IBM patients is correlated with exacerbated immune dysregulation and increased disease burden.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

et al. 2023

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“…(CG000086 Rev D), with a target of 7,500 to 25,000 cells from each sample and as previously published by us (68). The cells were suspended in 0.04% BSA in PBS and were loaded on the Chromium Single-Cell A Chip.…”

Section: Methodsmentioning

confidence: 99%

IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia

Huuhtanen¹,

Ilander²,

Yadav³

et al. 2022

Journal of Clinical Investigation

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“…13,14 Expression of TOX has been found in several types of lymphoma, including both B and T cell subtypes. 13,15,16 Huuhtanen et al 17 The goal of this study is to investigate the extent of TOX expression in T-LGLL cells, and whether TOX expression can be used to differentiate between T-LGLL cells and reactive T cells in bone marrow.…”

Section: Introductionmentioning

confidence: 99%

TOX as a new diagnostic marker for T cell large granular lymphocytic leukaemia

Burg,

Visser,

Diepstra

2023

Histopathology

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AimsT cell large granular lymphocytic leukaemia (T‐LGLL) is a rare disorder that may underlie otherwise unexplained cytopenias. The identification of T‐LGLL cells in bone marrow biopsies can be a challenge, because a robust immunohistochemistry marker is lacking. The markers currently in use (granzyme B, TIA‐1 and CD8) are difficult to interpret or lack specificity. Therefore, we investigated whether immunohistochemistry for thymocyte selection‐associated high‐mobility group box (TOX), a transcription factor that associates with chronic T cell stimulation, could be a reliable tool for the identification of T‐LGLL cells.Methods and resultsIn this retrospective study, expression of TOX in CD8+ cells in bone marrow biopsies of T‐LGLL patients (n = 38) was investigated and compared to bone marrow of controls with reactive T cell lymphocytosis (n = 10). All biopsies were evaluated for TOX staining within the CD8‐positive T cell population. The controls were essentially negative for TOX, whereas all T‐LGLL cases were positive (median = 80%, range = 10–100%), even when bone marrow involvement was subtle.ConclusionTOX is a highly sensitive marker for the neoplastic cells of T‐LGLL and we recommend its use, especially in the diagnostic work‐up of patients with unexplained cytopenias.

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Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia

Cited by 35 publications

References 69 publications

Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

Uncovering the significance of expanded CD8+ large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

IFN-α with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia

TOX as a new diagnostic marker for T cell large granular lymphocytic leukaemia

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