Reduced potency of cytotoxic T lymphocytes from patients with high-risk myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are a group of clonal bone marrow disorders, with dysplasia, cytopenias and increased risk of progression to acute myeloid leukemia. A dysregulated immune system precipitates MDS, and to gain insights into the relevance of cytotoxic T lymphocyte (CTL) in this process, we examined the frequency and function of CX3CR1- and CD57-positive T lymphocytes from MDS patients.
Materials and methods
Peripheral blood and/or bone marrow samples from 31 MDS patients and 12 healthy controls were examined by flow cytometry. Expression of cytotoxic granule constituents, immunological co-receptors, adhesion molecules and markers of activation were quantified on unstimulated lymphocytes. Degranulation, cytotoxicity and conjugate formation with target cells following co-culture of CTL with target cell lines or autologous bone marrow-derived CD34+ cells were quantified by flow cytometry.
CX3CR1 expression was increased in bone marrow from high-risk MDS patients compared to healthy controls. Expression of CD57 and CX3CR1 was closely correlated, identifying a CTL subset with high cytotoxic capacity. In vitro, TCR-induced redirected cytotoxicity was markedly decreased for high-risk MDS patients compared to controls. CTL from MDS patients with the lowest target cell cytotoxicity had reduced expression of adhesion molecules and formed fewer conjugates with target cells.
Although phenotypically defined CTL numbers were increased in the bone marrow of MDS patients, we found that CTL from high-risk MDS patients exhibited a lower TCR-induced redirected cytotoxic capacity. Thus, decreased T cell cytotoxicity seems related to reduced adhesion to target cells and may contribute to impaired anti-leukemic immune surveillance in MDS.
KeywordsMyelodysplastic syndromes Cytotoxic T lymphocytes CD57 CX3CR1 Granzyme B Adhesion
Acute myeloid leukemia
Bone marrow mononuclear cell
Cytotoxic T lymphocyte
International prognostic scoring system revised
Mann–Whitney U test
Refractory anemia with excess of blasts
Refractory anemia with ring sideroblasts
Refractory anemia with multilineage dysplasia
T regulatory cell
We thank Professor Einar Kristoffersen, Department of Clinical Science, University of Bergen for scientific advice, and Kristin Paulsen and Marie Hagen for technical assistance in the laboratory. We also thank Professor Kaoru Tohyama, Kobe University Graduate School of Medicine, Kobe, Japan, for generously supplying the MDS-L cell line. The flow cytometry for the cytotoxicity assay was performed at the Molecular Imaging Center, Dept. of Biomedicine, University of Bergen. This work was supported by the Western Norway Regional Health Authority (Helse Vest), University of Bergen and the Norwegian Cancer Society (Kreftforeningen).
K Sand performed research, analyzed and interpreted data and drafted the manuscript; J. Theorell performed research, interpreted data and drafted the manuscript; Ø. Bruserud designed research, interpreted data and drafted the manuscript; Y. Bryceson designed research, interpreted data and drafted the manuscript; and A. Olsnes Kittang designed research, provided patient material and clinical data, interpreted data, drafted the manuscript and was responsible for preparing the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
No potential conflicts of interest to disclose.
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