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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.


PubMed | Karolinska Institutet, Deutsches Rheuma Forschungszentrum A Leibniz Institute, University of Cambridge, University of Oslo and University of Paris Descartes
Type: Journal Article | Journal: 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 homozygousdeletion 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)- 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.


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.


Ni J.,German Cancer Research Center | Holsken O.,German Cancer Research Center | Miller M.,German Cancer Research Center | Hammer Q.,Deutsches Rheuma Forschungszentrum A Leibniz Institute | And 3 more authors.
OncoImmunology | Year: 2016

Natural killer (NK) cell infusions can induce remissions in subsets of patients with different types of cancer. The optimal strategies for NK cell activation prior to infusion are still under debate. There is recent evidence that NK cells can acquire long-term functional competence by preactivation with the cytokines IL-12/15/18. The mechanisms supporting the maintenance of long-term NK cell antitumor activity are incompletely under-stood. Here, we show that NK cells preactivated in vitro with IL-12/15/18, but not with IL-15 alone, maintained high antitumor activity even 1 mo after transfer into lymphopenic RAG-2−/−γc−/− mice. The NK cell intrinsic ability for IFNγ production coincided with demethylation of the conserved non-coding sequence (CNS) 1 in the Ifng locus, previously shown to enhance transcription of Ifng. In a xenograft melanoma mouse model, human IL-12/15/18-preactivated NK cells rejected tumors more efficiently. In RAG-2−/−γc−/− mice, co-transfer of CD4+ T cells further improved the long-term competence of NK cells for IFNγ production that was dependent on IL-2. CD4+ T cell activation during homeostatic proliferation required macrophages and further promoted the long-term NK cell antitumor activity. Thus, NK cells can “remember” a previous exposure to cytokines by epigenetic imprinting resulting in a remarkable stability of the IFNγ-producing phenotype after adoptive transfer. In addition, our results support combination of cytokine-preactivated NK cells with CD4+ T cell activation upon lymphopenic conditioning to achieve long-term NK cell effector function for cancer immunotherapy. © 2016 Taylor & Francis Group, LLC.


Stervbo U.,Charité - Medical University of Berlin | Stervbo U.,Deutsches Rheuma Forschungszentrum a Leibniz Institute | Stervbo U.,Ruhr University Bochum | Bozzetti C.,Charité - 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.


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.


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 (T(H)1) 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 T(H)1 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 NKG2C(hi) 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.


PubMed | Saarland University and Deutsches Rheuma Forschungszentrum A Leibniz Institute
Type: Journal Article | Journal: PLoS pathogens | Year: 2014

Memory type 1 T helper (T(H)1) cells are characterized by the stable expression of interferon (IFN)- 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-. 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 T(H)1 cells. The accessibility of the CNS1 was required to enhance IFN- transcriptional activity in response to NKG2C and 2B4 engagement, which led to consistent IFN- production in NKG2C(hi) NK cells. Thus, our data identify epigenetic imprinting of the IFNG locus as selective hallmark and crucial mechanism driving strong and stable IFN- expression in HCMV-specific NK cell expansions, providing a molecular basis for the regulation of adaptive features in innate cells.


PubMed | German Cancer Research Center and Deutsches Rheuma Forschungszentrum A Leibniz Institute
Type: Journal Article | Journal: Oncoimmunology | Year: 2016

Natural killer (NK) cell infusions can induce remissions in subsets of patients with different types of cancer. The optimal strategies for NK cell activation prior to infusion are still under debate. There is recent evidence that NK cells can acquire long-term functional competence by preactivation with the cytokines IL-12/15/18. The mechanisms supporting the maintenance of long-term NK cell antitumor activity are incompletely under-stood. Here, we show that NK cells preactivated


PubMed | Deutsches Rheuma ForschungsZentrum a Leibniz Institute
Type: Journal Article | Journal: European journal of immunology | Year: 2012

B cells and regulatory T (Treg) cells can both facilitate remission from experimental auto immune encephalomyelitis (EAE), a disease of the central nervous system (CNS) used as a model for multiple sclerosis (MS). Considering that B-cell-depletion therapy (BCDT) is used to treat MS patients, we asked whether Treg-cell activation depended on B cells during EAE. Treg-cell proliferation, accumulation in CNS, and augmentation of suppressive activity in the CNS were normal in B-cell-deficient mice, indicating that B cells are not essential for activation of the protective Treg-cell response and thus provide an independent layer of regulation. This function of B cells involved early suppression of the encephalitogenic CD4(+) T-cell response, which was enhanced in B-cell-deficient mice. CD4(+) T-cell depletion was sufficient to intercept the transition from acute-to-chronic EAE when applied to B-cell-deficient animals that just reached the peak of disease severity. Intriguingly, this treatment did not improve disease when applied later, implying that chronic disability was ultimately maintained independently of pathogenic CD4(+) T cells. Collectively, our data indicate that BCDT is unlikely to impair Treg-cell function, yet it might produce undesirable effects on T-cell-mediated autoimmune pathogenesis.

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