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NK cell memory

Miljana Radenkovic, Kristina Uvebrant, Oskar Skog, Luis Sarmiento, Jeanette Avartsson, Peter Storm, Petter Vickman, Per-Anders Bertilsson, Malin Fex, Olle Korsgren, Corrado M Cilio
The current view of type 1 diabetes (T1D) is that it is an immune-mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated to human islets of non-diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n=38) was employed to identify alpha, beta, T, NK and B cells...
October 26, 2016: Clinical and Experimental Immunology
Todd A Fehniger, Megan A Cooper
Due to their ability to kill cancer cells and produce proinflammatory cytokines, natural killer (NK) cells have long been of clinical interest for their antitumor properties. The recent discovery of NK cell memory demonstrates that NK cell functions, and potentially antitumor responses, can be enhanced long term. Following nonspecific activation with the cytokines IL-12, IL-15, and IL-18 or in response to antigens or cytomegalovirus (CMV), human and mouse NK cells exhibit stable, enhanced functional responses with phenotypic and molecular changes...
October 20, 2016: Trends in Immunology
Aida S Hansen, Bettina B Bundgaard, Bjarne K Møller, Per Höllsberg
CD46 is a glycoprotein with important functions in innate and adaptive immune responses. Functionally different isoforms are generated by alternative splicing at exons 7-9 (BC and C isoforms) and exon 13 (CYT-1 and CYT-2 isoforms) giving rise to BC1, BC2, C1 and C2. We developed a novel real-time PCR assay that allows quantitative comparisons between these isoforms. Their relative frequency in CD4(+) T cells from 100 donors revealed a distribution with high interpersonally variability. Importantly, the distribution between the isoforms was not random and although splicing favoured inclusion of exon 8 (BC isoforms), exclusion of exon 8 (C isoforms) was significantly linked to exclusion of exon 13 (CYT-2 isoforms)...
October 14, 2016: Scientific Reports
Lexus R Johnson, Orr-El Weizman, Moritz Rapp, Sing Sing Way, Joseph C Sun
Despite robust secondary T cell expansion primed by vaccination, the impact on primary immune responses to heterotypic antigens remains undefined. Here we show that secondary expansion of epitope-specific memory CD8(+) T cells primed by prior infection with recombinant pathogens limits the primary expansion of naive CD8(+) T cells with specificity to new heterologous antigens, dampening protective immunity against subsequent pathogen challenge. The degree of naive T cell repression directly paralleled the magnitude of the recall response...
October 11, 2016: Cell Reports
María Del Mar Valenzuela-Membrives, Francisco Perea-García, Abel Sanchez-Palencia, Francisco Ruiz-Cabello, Mercedes Gómez-Morales, María Teresa Miranda-León, Inmaculada Galindo-Angel, María Esther Fárez-Vidal
Immune cell infiltration is a common feature of many human solid tumors. Innate and adaptative immune systems contribute to tumor immunosurveillance. We investigated whether tumors evade immune surveillance by inducing states of tolerance and/or through the inability of some immune subpopulations to effectively penetrate tumor nests. Immunohistochemistry and flow cytometry analysis were used to study the composition and distribution of immune subpopulations in samples of peripheral blood, tumor tissue (TT), adjacent tumor tissue (ATT), distant non-tumor tissue (DNTT), cancer nests, cancer stroma, and invasive margin in 61 non-small-cell lung cancer (NSCLC) patients...
September 26, 2016: Oncotarget
Mariella Della Chiesa, Silvia Pesce, Letizia Muccio, Simona Carlomagno, Simona Sivori, Alessandro Moretta, Emanuela Marcenaro
Human NK cells are distinguished into CD56(bright)CD16(-) cells and CD56(dim)CD16(+) cells. These two subsets are conventionally associated with differential functional outcomes and are heterogeneous with respect to the expression of KIR and CD94/NKG2 heterodimers that represent the two major types of HLA-class I-specific receptors. Recent studies indicated that immature CD56(bright) NK cells, homogeneously expressing the inhibitory CD94/NKG2A receptor, are precursors of CD56(dim) NK cells that, in turn, during their process of differentiation, lose expression of CD94/NKG2A and subsequentially acquire inhibitory KIRs and LIR-1...
2016: Frontiers in Immunology
Petra Cerkovnik, Barbara Jezeršek Novaković, Vida Stegel, Srdjan Novaković
In our previous studies, it has been demonstrated that in more than 80% of mice long-lasting antitumor immunity has been established following intraperitoneal (i.p.) vaccination with tumor vaccine composed of irradiated syngeneic tumor cells and CpG ODNs class C. The aim of this study was, therefore, to investigate molecular mechanisms through which this vaccine triggers the immunity and to define genes particularly involved in this process. Changes in gene expression were followed in mononuclear cells isolated from peritoneal lavages, spleens and bone marrow samples...
September 24, 2016: Molecular Immunology
Luhua H Zhang, June Ho Shin, Mikel D Haggadone, John B Sunwoo
A tissue-resident population of natural killer cells (NK cells) in the liver has recently been described to have the unique capacity to confer immunological memory in the form of hapten-specific contact hypersensitivity independent of T and B cells. Factors regulating the development and maintenance of these liver-resident NK cells are poorly understood. The aryl hydrocarbon receptor (AhR) is a transcription factor modulated by exogenous and endogenous ligands that is important in the homeostasis of immune cells at barrier sites, such as the skin and gut...
September 26, 2016: Journal of Experimental Medicine
Michael J Haller, Stephen E Gitelman, Peter A Gottlieb, Aaron W Michels, Daniel J Perry, Andrew R Schultz, Maigan A Hulme, Jonathan J Shuster, Baiming Zou, Clive H Wasserfall, Amanda Posgai, Clayton E Mathews, Todd M Brusko, Mark A Atkinson, Desmond A Schatz
Low-dose anti-thymocyte globulin (ATG) + pegylated granulocyte-colony stimulating factor (G-CSF) preserves beta cell function for at least 12-months in type 1 diabetes (T1D). Herein, we describe metabolic and immunologic parameters 24-months following treatment. Patients with established T1D (duration 4-24 months) were randomized to ATG and peg-G-CSF (N=17) or placebo (N=8). Primary outcomes included AUC C-peptide following mixed-meal tolerance test (MMTT) and flow cytometry. "Responders" (12-month C-peptide ≥ baseline), "Super-responders" (24-month C-peptide ≥ baseline), and "Non-responders" (12-month C-peptide < baseline) were evaluated for biomarkers of outcome...
September 26, 2016: Diabetes
Yalei Liu, Ran You, Nan Yu, Yan Gong, Chenxue Qu, Yang Zhang, Guizhi Lu, Youyuan Huang, Hong Zhang, Ying Gao, Yanming Gao, Xiaohui Guo
Both cellular and humoral responses play important roles in the pathogenesis of Hashimoto's thyroiditis (HT). However, the immunological differences between euthyroid (mild HT) and hypothyroid (severe HT) patients are unknown. This study aimed to investigate the distribution of lymphocyte subsets and cytokine profiles in HT patients with differences in thyroid function. Peripheral blood was drawn from 18 healthy controls and 54 HT patients (33 patients with mild HT, 21 patients with severe HT). The percentages of B cell subsets, T cell subsets and NK cells were analyzed by flow cytometry...
September 23, 2016: International Immunopharmacology
Joyce Lübbers, Marian H van Beers-Tas, Saskia Vosslamber, Samina A Turk, Sander de Ridder, Elise Mantel, John G Wesseling, Martine Reijm, Ingrid M van Hoogstraten, Johannes W Bijlsma, Dirkjan van Schaardenburg, Hetty J Bontkes, Cornelis L Verweij
BACKGROUND: Multiple lymphocyte subsets like T and B cells have been connected to joint infiltration and inflammation in rheumatoid arthritis (RA). Identification of leucocyte subsets that are dysregulated in arthritis development could provide insight into the aetiology of RA. This study aimed to investigate the composition of the peripheral blood components, i.e. CD14(+) monocytes, CD4(+) and CD8(+) T lymphocytes (CD3(+)), CD80(+), C-X-C chemokine receptor 3 (CXCR3)(+) and CD27(+) B lymphocytes (CD19(+)), CD16(+)CD56(+)CD3(-) natural killer (NK) cells and activated CD56(+)CD3(+) T cells, for association with arthritis development in patients with arthralgia...
2016: Arthritis Research & Therapy
Matthias Braun, Marie L Ress, Young-Eun Yoo, Claus J Scholz, Matthias Eyrich, Paul G Schlegel, Matthias Wölfl
Interleukin 12 (IL12) is a key inflammatory cytokine critically influencing Th1/Tc1-T-cell responses at the time of initial antigen encounter. Therefore, it may be exploited for cancer immunotherapy. Here, we investigated how IL12, and other inflammatory cytokines, shape effector functions of human T-cells. Using a defined culture system, we followed the gradual differentiation and function of antigen-specific CD8(+) T cells from their initial activation as naïve T cells through their expansion phase as early memory cells to full differentiation as clonally expanded effector T cells...
July 2016: Oncoimmunology
Eun-Mi Kim, Eun-Hee Lee, Hwa-Yeon Lee, Ha-Rim Choi, Kon-Young Ji, Su-Man Kim, Kwang Dong Kim, Hyung-Sik Kang
Natural killer (NK) cells have been well known to play a critical role in innate immunity, but they are also capable of regulating adaptive immunity through the induction of T cell-mediated memory response and B cell-mediated autoimmune response. NK cells are differentiated from hematopoietic stem cells (HSCs) in the bone marrow (BM), and a series of surface molecules are expressed on NK cells in a differentiation stage-specific manner. Axl receptor tyrosine kinase is originally identified as homeostatic regulators for antigen-presenting cells, and its ligand, growth-arrest-specific gene 6 (Gas6), has been reported to promote cell survival, proliferation, and migration, but their regulatory role in the development and effector function of NK cells is not yet fully understood...
August 22, 2016: Protoplasma
Dhifaf Sarhan, Frank Cichocki, Bin Zhang, Ashley Yingst, Stephen R Spellman, Sarah Cooley, Michael R Verneris, Bruce R Blazar, Jeffrey S Miller
Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immunoregulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor T-cell Ig and ITIM domain (TIGIT), which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome...
October 1, 2016: Cancer Research
Jacquelyn Freund, Rebecca M May, Enjun Yang, Hongchuan Li, Matthew McCullen, Bin Zhang, Todd Lenvik, Frank Cichocki, Stephen K Anderson, Taku Kambayashi
It has recently been appreciated that NK cells exhibit many features reminiscent of adaptive immune cells. Considerable heterogeneity exists with respect to the ligand specificity of individual NK cells and as such, a subset of NK cells can respond, expand, and differentiate into memory-like cells in a ligand-specific manner. MHC I-binding inhibitory receptors, including those belonging to the Ly49 and KIR families, are expressed in a variegated manner, which creates ligand-specific diversity within the NK cell pool...
August 2016: PLoS Biology
Tsukasa Nabekura, Lewis L Lanier
Natural killer (NK) cells are important in host defense against pathogens, and they can subsequently differentiate into memory NK cells. The Ly49 and KIR gene families in rodents and humans encode both inhibitory and activating receptors for MHC class I. The physiological role of activating KIR or Ly49 receptors that recognize self-MHC class I during immune response to viral infections is unknown. Here, we address how the activating Ly49D receptor impacts the NK cell response to mouse cytomegalovirus (MCMV) infection by comparing the activation and differentiation of Ly49D-bearing NK cells in mice lacking or expressing H-2D(d), the cognate MHC class I ligand of Ly49D...
July 19, 2016: Immunity
Enrico Lugli, Kelly Hudspeth, Alessandra Roberto, Domenico Mavilio
Efficient immune responses to invading pathogens are the result of the complex but coordinated synergy between a variety of cell types from both the innate and adaptive arms of the immune system. While adaptive and innate immune responses are highly complementary, some cells types within these two systems perform similar functions, underscoring the need for redundancy and increased flexibility. In this review, we will discuss the striking shared features of immunological memory and tissue residency recently discovered between T cells, a component of the adaptive immune system, and natural killer (NK) cells, members generally assigned to the innate compartment...
August 2016: European Journal of Immunology
Maren Q DeGottardi, Afam A Okoye, Mukta Vaidya, Aarthi Talla, Audrie L Konfe, Matthew D Reyes, Joseph A Clock, Derick M Duell, Alfred W Legasse, Amit Sabnis, Byung S Park, Michael K Axthelm, Jacob D Estes, Keith A Reiman, Rafick-Pierre Sekaly, Louis J Picker
IL-15 has been implicated as a key regulator of T and NK cell homeostasis in multiple systems; however, its specific role in maintaining peripheral T and NK cell populations relative to other γ-chain (γc) cytokines has not been fully defined in primates. In this article, we address this question by determining the effect of IL-15 inhibition with a rhesusized anti-IL-15 mAb on T and NK cell dynamics in rhesus macaques. Strikingly, anti-IL-15 treatment resulted in rapid depletion of NK cells and both CD4(+) and CD8(+) effector memory T cells (TEM) in blood and tissues, with little to no effect on naive or central memory T cells...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Liu-Sheng Peng, Fang-Yuan Mao, Yong-Liang Zhao, Ting-Ting Wang, Na Chen, Jin-Yu Zhang, Ping Cheng, Wen-Hua Li, Yi-Pin Lv, Yong-Sheng Teng, Gang Guo, Ping Luo, Weisan Chen, Quan-Ming Zou, Yuan Zhuang
CD3+CD56+ natural killer T (NKT)-like cells are a group of CD3+ T cells sharing characteristics of NK and T cells and constitute a major component of host anti-tumor immune response in human cancer. However, the nature, function and clinical relevance of CD3+CD56+ NKT-like cells in human gastric cancer (GC) remain unclear. In this study, we showed that the frequencies of CD3+CD56+NKT-like cells in GC tumors were significantly decreased and low levels of tumor-infiltrating CD3+CD56+ NKT-like cells were positively correlated with poor survival and disease progression...
July 8, 2016: Oncotarget
Greg D Whitehill, Shoba Amarnath, Pawel Muranski, Keyvan Keyvanfar, Minoo Battiwalla, Austin J Barrett, Dhanalakshmi Chinnassamy
Selective depletion (SD) of alloreactive T cells from allogeneic hematopoeitic stem cell transplants to prevent graft-versus-host disease (GVHD) without compromising immune reconstitution and antitumor responses remains a challenge. Here, we demonstrate a novel SD strategy whereby alloreacting T cells are efficiently deleted ex vivo with adenosine. SD was achieved in human leukocyte antigen (HLA) mismatched cocultures by multiple exposures to 2 mmol/l adenosine over 7 days. Adenosine depleted greater than to 90% of alloproliferating T cells in mismatched, haploidentical, and matched sibling pairs while conserving response to third-party antigens...
September 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
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