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Liu L.L.,Karolinska Institutet | Landskron J.,University of Oslo | Ask E.,University of Oslo | Enqvist M.,Karolinska Institutet | And 17 more authors.
Cell Reports | Year: 2016

Infection by human cytomegalovirus (HCMV) leads to NKG2C-driven expansion of adaptive natural killer (NK) cells, contributing to host defense. However, approximately 4% of all humans carry a homozygous deletion of the gene that encodes NKG2C (NKG2C -/-). Assessment of NK cell repertoires in 60 NKG2C -/- donors revealed a broad range of NK cell populations displaying characteristic footprints of adaptive NK cells, including a terminally differentiated phenotype, functional reprogramming, and epigenetic remodeling of the interferon (IFN)-γ promoter. We found that both NKG2C- and NKG2C+ adaptive NK cells expressed high levels of CD2, which synergistically enhanced ERK and S6RP phosphorylation following CD16 ligation. Notably, CD2 co-stimulation was critical for the ability of adaptive NK cells to respond to antibody-coated target cells. These results reveal an unexpected redundancy in the human NK cell response to HCMV and suggest that CD2 provides "signal 2" in antibody-driven adaptive NK cell responses. Liu et al. demonstrate the emergence of redundant adaptive NK cell subsets in NKG2C-/- donors. Functional studies unraveled a critical role for CD2 in antibody-dependent responses by adaptive NK cells, paving the way for new strategies to harness their cytotoxic potential in cell therapy. © 2016 The Authors. Source


Stervbo U.,Charite - Medical University of Berlin | Stervbo U.,Deutsches Rheuma Forschungszentrum A Leibniz Institute | Stervbo U.,Ruhr University Bochum | Bozzetti C.,Charite - Medical University of Berlin | And 14 more authors.
Age | Year: 2015

Immunosenescence results from a continuous deterioration of immune responses resulting in a decreased response to vaccines. A well-described age-related alteration of the immune system is the decrease of de novo generation of T and B cells. In addition, the accumulation of memory cells and loss of diversity in antigen specificities resulting from a lifetime of exposure to pathogens has also been described. However, the effect of aging on subsets of γδTCR+ T cells and Tregs has been poorly described, and the efficacy of the recall response to common persistent infections in the elderly remains obscure. Here, we investigated alterations in the subpopulations of the B and T cells among 24 healthy young (aged 19–30) and 26 healthy elderly (aged 53–67) individuals. The analysis was performed by flow cytometry using freshly collected peripheral blood. γδTCR+ T cells were overall decreased, while CD4+CD8− cells among γδTCR+ T cells were increased in the elderly. Helios+Foxp3+ and Helios−Foxp3+ Treg cells were unaffected with age. Recent thymic emigrants, based on CD31 expression, were decreased among the Helios+Foxp3+, but not the Helios−Foxp3+ cell populations. We observed a decrease in Adenovirus-specific CD4+ and CD8+ T cells and an increase in CMV-specific CD4+ T cells in the elderly. Similarly, INFγ+TNFα+ double-positive cells were decreased among activated T cells after Adenovirus stimulation but increased after CMV stimulation. The data presented here indicate that γδTCR+ T cells might stabilize B cells, and functional senescence might dominate at higher ages than those studied here. © 2015, American Aging Association. Source


Stervbo U.,Charite - Medical University of Berlin | Stervbo U.,Deutsches Rheuma Forschungszentrum A Leibniz Institute | Stervbo U.,Ruhr University Bochum | Meier S.,Charite - Medical University of Berlin | And 15 more authors.
Age | Year: 2015

Immunosenescence is a hallmark of the aging immune system, leading to increased susceptibility to infections in the aged population and decreased ability to eradicate infectious pathogens. These effects, in turn, result in an increased burden on the healthcare system due to elevated frequency and duration of hospital visits. Growing evidence suggests that cells of the innate immune system are central modulators for the initiation and maintenance of an adequate pathogen-specific response through the adaptive immune system. While there are many reports on age-dependent alterations and dysfunctions of the adaptive immune system, the underlying mechanisms and effects of natural aging on the composition of the innate immune system remain unknown. Here, we present the results obtained from the comprehensive immunophenotyping of innate leukocyte populations, examined for age-related alterations within different sub-populations assessed using multi-parametric flow cytometry. We compared peripheral blood mononuclear cells from 24 young (aged 19–30 years) and 26 elderly (aged 53–67 years) donors. For classical CD16+CD56dim NK cells, the fraction of CD62L+CD57+ was diminished in the elderly donors compared with young individuals, while the other investigated NK subsets remained unaffected by age. Both transitional monocytes and non-classical CD14+–CD16++ monocytes were increased in the elderly compared with the young. The populations of pDCs and mDC2 were decreased among the elderly. These data demonstrate that the dynamics of the mDC subsets might counteract decreased virus surveillance. Furthermore, these data show that the maturation of NK cells might gradually slow down. © 2015, American Aging Association. Source


Romagnani C.,Deutsches Rheuma Forschungszentrum A Leibniz Institute | Babic M.,Deutsches Rheuma Forschungszentrum A Leibniz Institute | Babic M.,University of Rijeka
European Journal of Immunology | Year: 2014

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency, which is characterized by abnormal immune system functions caused by the lack of expression of WAS protein (WASp). A higher tumor susceptibility is observed in WAS patients; whether this is a direct consequence of impaired immunosurveillance due to WAS deficiency in immune cells is, however, an open question. In this issue of the European Journal of Immunology, Catucci et al. [Eur. J. Immunol. 2014. 44: 1039-1045] shed light on the link between Was deficiency and immunosurveillance in a tumor-prone mouse model and report a role for the impaired crosstalk between natural killer (NK) cells and dendritic cells (DCs) in mediating this process. The potential mechanisms involved in WASp regulation of NK/DC-mediated immunosurveillance are the focus of this Commentary. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Luetke-Eversloh M.,Deutsches Rheuma Forschungszentrum A Leibniz Institute | Hammer Q.,Deutsches Rheuma Forschungszentrum A Leibniz Institute | Durek P.,Deutsches Rheuma Forschungszentrum A Leibniz Institute | Nordstrom K.,Saarland University | And 7 more authors.
PLoS Pathogens | Year: 2014

Memory type 1 T helper (TH1) cells are characterized by the stable expression of interferon (IFN)-γ as well as by the epigenetic imprinting of the IFNG locus. Among innate cells, NK cells play a crucial role in the defense against cytomegalovirus (CMV) and represent the main source of IFN-γ. Recently, it was shown that memory-like features can be observed in NK cell subsets after CMV infection. However, the molecular mechanisms underlying NK cell adaptive properties have not been completely defined. In the present study, we demonstrated that only NKG2Chi NK cells expanded in human CMV (HCMV) seropositive individuals underwent epigenetic remodeling of the IFNG conserved non-coding sequence (CNS) 1, similar to memory CD8+ T cells or TH1 cells. The accessibility of the CNS1 was required to enhance IFN-γ transcriptional activity in response to NKG2C and 2B4 engagement, which led to consistent IFN-γ production in NKG2Chi NK cells. Thus, our data identify epigenetic imprinting of the IFNG locus as selective hallmark and crucial mechanism driving strong and stable IFN-γ expression in HCMV-specific NK cell expansions, providing a molecular basis for the regulation of adaptive features in innate cells. © 2014 Luetke-Eversloh et al. Source

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