Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes
| Autor: | Andrea Kündgen, Xiaoyi Zhao, Kathrin Schönberg, Angela R. Manser, Markus Uhrberg, Julia Fröbel, Maryam Hejazi, Norbert Gattermann, Ulrich Germing, Rainer Haas |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Cytotoxicity Immunologic Male Interleukin 2 chemical and pharmacologic phenomena Immunophenotyping Natural killer cell Natural killer cell differentiation medicine Humans Cytotoxic T cell Lymphocyte Count Receptor Aged Aged 80 and over Lymphokine-activated killer cell biology Cell Differentiation Articles Hematology Middle Aged Prognosis Natural killer T cell Killer Cells Natural Phenotype medicine.anatomical_structure Granzyme Case-Control Studies Myelodysplastic Syndromes Immunology biology.protein Interleukin-2 Female medicine.drug |
| Zdroj: | Haematologica. 100:643-652 |
| ISSN: | 1592-8721 0390-6078 |
| DOI: | 10.3324/haematol.2014.118679 |
| Popis: | Natural killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. One subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count10/mm(3) blood) with normal frequencies of T and natural killer-like T cells. Natural killer cell-deficient patients were predominantly found in high-risk subgroups and deficiency of these cells was significantly associated with poor prognosis. In the second subgroup, comprising the majority of patients (76%), natural killer cells were present but exhibited poor cytotoxicity. The defect was strongly associated with reduced levels of perforin and granzyme B. Notably, natural killer cell function and arming of cytotoxic granules could be fully reconstituted by in vitro stimulation. Further phenotypic analysis of these patients revealed an immature natural killer cell compartment that was biased towards CD56(bright) cells. The residual CD56(dim) cells exhibited a significant increase of the unlicensed NKG2A(-)KIR(-) subset and a striking reduction in complexity of the repertoire of killer cell immunoglobulin-like receptors. Taken together, these results suggest that the widespread defects in natural killer cell function occurring in patients with myelodysplastic syndromes are mostly due to either unsuccessful or inefficient generation of mature, functionally competent natural killer cells, which might contribute to disease progression through impaired immune surveillance. |
| Databáze: | OpenAIRE |
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