scholarly journals Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2

2013 ◽  
Vol 210 (6) ◽  
pp. 1153-1165 ◽  
Author(s):  
Jonathan Sitrin ◽  
Aaron Ring ◽  
K. Christopher Garcia ◽  
Christophe Benoist ◽  
Diane Mathis
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Interferon Γ ◽  
Cell Axis ◽  
Cell Functions

Regulatory T (T reg) cells control progression to autoimmune diabetes in the BDC2.5/NOD mouse model by reining in natural killer (NK) cells that infiltrate the pancreatic islets, inhibiting both their proliferation and production of diabetogenic interferon-γ. In this study, we have explored the molecular mechanisms underlying this NK–T reg cell axis, following leads from a kinetic exploration of gene expression changes early after punctual perturbation of T reg cells in BDC2.5/NOD mice. Results from gene signature analyses, quantification of STAT5 phosphorylation levels, cytokine neutralization experiments, cytokine supplementation studies, and evaluations of intracellular cytokine levels collectively argue for a scenario in which T reg cells regulate NK cell functions by controlling the bioavailability of limiting amounts of IL-2 in the islets, generated mainly by infiltrating CD4+ T cells. This scenario represents a previously unappreciated intertwining of the innate and adaptive immune systems: CD4+ T cells priming NK cells to provoke a destructive T effector cell response. Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets.

NK-dependent DC maturation is mediated by TNFα and IFNγ released upon engagement of the NKp30 triggering receptor

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 566-571 ◽  
Author(s):  
Massimo Vitale ◽  
Mariella Della Chiesa ◽  
Simona Carlomagno ◽  
Daniela Pende ◽  
Maurizio Aricò ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nk Cell ◽  
Interferon Γ ◽  
Cell Functions ◽  
Relevant Role ◽  
Factor Α ◽  
Necrosis Factor ◽  
Dc Maturation

Abstract Natural killer (NK) cells were recently shown to play a relevant role in the process of dendritic cell (DC) maturation. This function is exerted either by direct DC stimulation or through killing those DCs that did not properly acquire a mature phenotype. While killing of immature DCs is dependent on the function of the NKp30 triggering receptor, the mechanism by which NK cells induce DC maturation is still unclear. In this study, we show that also the NK-mediated induction of DC maturation is dependent on NKp30. Upon NK/DC interaction, resulting in NKp30 engagement, NK cells produced tumor necrosis factor α (TNFα) (and interferon γ [IFNγ]) that, in turn, promoted DC maturation. Masking of NKp30 with specific monoclonal antibodies (mAbs) strongly reduced maturation of DCs cocultured with NK cells. In addition, supernatant from NK cells stimulated via NKp30 induced DC maturation, and this effect was neutralized by anti-TNFα antibodies (Abs). This NKp30 function is controlled by the HLA-specific inhibitory NK receptors. Accordingly, the ability to promote maturation was essentially confined to NK cells expressing the killer immunoglobulin-like receptor–negative (KIR–) NKG2Adull phenotype. Finally, the analysis of perforin-deficient NK cells allowed the dissection of the 2 NKp30-mediated NK-cell functions, since NKp30 could induce cytokine-dependent DC maturation in the absence of NK-mediated DC killing.

scholarly journals HLA-E Up-Regulation Induced by HIV Infection May Directly Contribute to CD94-Mediated Impairment of NK Cells

2005 ◽  
Vol 18 (2) ◽  
pp. 269-276 ◽  
Author(s):  
F. Martini ◽  
C. Agrati ◽  
G. D'Offizi ◽  
F. Poccia
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Treatment Interruption ◽  
Cell Number ◽  
Hiv Replication

Alterations in NK cell numbers and function have been repeatedly shown during HIV infection. In this study, NK cell number and MHC class I expression on CD4+ T cells were studied in HIV patients at different stages of disease progression. An increased expression of HLA-E was seen on CD4+ T cells. In parallel, a reduced number of CD94+ NK cells was observed in advanced disease stages. Moreover, a decline in CD94 expression on NK cells was observed at the HIV replication peak in patients undergoing antiretroviral treatment interruption, suggesting a role of viral replication on NK cells alterations. In vitro HIV infection induced a rapid down-regulation of HLA-A,B,C expression, paralleled by an increased expression of HLA-E surface molecules, the formal ligands of CD94 NK receptors. HIV-infected HLA-E expressing cells were able to inhibit NK cell cytotoxicity through HLA-E expression, since cytotoxicity was restored by antibody masking experiments. These data indicate that the CD94/HLA-E interaction may contribute to NK cell dysfunction in HIV infection, suggesting a role of HIV replication in this process.

Elevated CD54 Expression Renders CD4+ T Cells Susceptible to Natural Killer Cell-Mediated Killing

2019 ◽  
Vol 220 (12) ◽  
pp. 1892-1903 ◽  
Author(s):  
Xi Chen ◽  
Huihui Chen ◽  
Zining Zhang ◽  
Yajing Fu ◽  
Xiaoxu Han ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Adaptive Immune Response ◽  
Phenotypic Analysis

Abstract Background Natural killer (NK) cells are an important type of effector cell in the innate immune response, and also have a role in regulation of the adaptive immune response. Several studies have indicated that NK cells may influence CD4+ T cells during HIV infection. Methods In total, 51 HIV-infected individuals and 15 healthy controls participated in this study. We performed the flow cytometry assays and real-time PCR for the phenotypic analysis and the functional assays of NK cell-mediated deletion of CD4+ T cells, phosphorylation of nuclear factor-κB (NF-κB/p65) and the intervention of metformin. Results Here we detected high CD54 expression on CD4+ T cells in HIV-infected individuals, and demonstrate that upregulated CD54 is associated with disease progression in individuals infected with HIV. We also show that CD54 expression leads to the deletion of CD4+ T cells by NK cells in vitro, and that this is modulated by NF-κB/p65 signaling. Further, we demonstrate that metformin can suppress CD54 expression on CD4+ T cells by inhibiting NF-κB/p65 phosphorylation. Conclusions Our data suggest that further studies to evaluate the potential role of metformin as adjunctive therapy to reconstitute immune function in HIV-infected individuals are warranted.

Tumor-induced suppression of interferon-γ production and enhancement of interleukin-10 production by natural killer (NK) cells: paralleled to CD4+ T cells

2005 ◽  
Vol 42 (9) ◽  
pp. 1023-1031 ◽  
Author(s):  
Haiming Wei ◽  
Xiaodong Zheng ◽  
Derming Lou ◽  
Liang Zhang ◽  
Ruijun Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cd4 T Cells ◽  
Interleukin 10 ◽  
Interferon Γ

scholarly journals KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4370-4376 ◽  
Author(s):  
Sarah Cooley ◽  
Valarie McCullar ◽  
Rosanna Wangen ◽  
Tracy L. Bergemann ◽  
Stephen Spellman ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Clinical Outcomes ◽  
Hematopoietic Cell Transplantation ◽  
Cell Function ◽  
Nk Cell ◽  
Interferon Γ ◽  
Unrelated Donor ◽  
Ifn Γ

Although unrelated hematopoietic cell transplantation (HCT) is curative for many hematologic malignancies, complications and relapse remain challenging obstacles. Natural killer (NK) cells, which recover quickly after transplantation, produce cytokines and express killer immunoglobulin-like receptors (KIRs) that regulate their cytotoxicity. Some clinical trials based on a KIR ligand mismatch strategy are associated with less relapse and increased survival, but results are mixed. We hypothesized that T cells in the graft may affect NK cell function and KIR expression after unrelated transplantation and that these differences correlate with clinical outcomes. NK cell function was evaluated using 77 paired samples from the National Marrow Donor Program Research Repository. Recipient NK cells at 100 days after both unmanipulated bone marrow (UBM) and T-cell depleted (TCD) transplants were compared with NK cells from their healthy donors. NK cells expressed fewer KIRs and produced more interferon γ (IFN-γ) after UBM compared to TCD transplants. Multivariate models showed that increased NK cell IFN-γ production correlated with more acute graft-versus-host disease (GVHD), and decreased KIR expression correlated with inferior survival. These results support the notion that T cells in the graft affect NK cell reconstitution in vivo. Understanding these mechanisms may result in strategies to improve clinical outcomes from unrelated HCT.

scholarly journals NK Cell Induced T Cell Anergy Depends on GRAIL Expression

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 790
Author(s):  
Grazyna Galazka ◽  
Malgorzata Domowicz ◽  
Alicja Ewiak-Paszynska ◽  
Anna Jurewicz
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Regulatory Function ◽  
T Cell Proliferation ◽  
Thymidine Uptake ◽  
Cell Expression

NK cells (natural killer cells) being a part of the innate immune system have been shown to be involved in immunoregulation of autoimmune diseases. Previously we have shown that HINT1/Hsp70 treatment induced regulatory NK cells ameliorating experimental autoimmune encephalomyelitis (EAE) course and CD4+ T cells proliferation. NK cells were isolated from mice treated with HINT1/Hsp70 and co-cultured with proteolipid protein (PLP)-stimulated CD4+ T cells isolated from EAE mice. Cell proliferation was assessed by thymidine uptake, cytotoxicity by lactate dehydrogenase (LDH) release assay and fluorescence activated cell sorting (FACS) analysis, protein expression by Western blot, mRNA by quantitative RT-PCR. Gene related to anergy in lymphocytes (GRAIL) expression was downregulated by specific siRNA and GRAIL overexpression was induced by pcDNA-GRAIL transfection. HINT1/Hsp70 pretreatment of EAE SJL/J mice ameliorated EAE course, suppressed PLP-induced T cell proliferation by enhancing T cell expression of GRAIL as GRAIL downregulation restored T cell proliferation. HINT1/Hsp70 treatment induced immunoregulatory NK cells which inhibited PLP-stimulated T cell proliferation not depending on T cell necrosis and apoptosis. This immunoregulatory NK cell function depended on NK cell expression of GRAIL as GRAIL downregulation diminished inhibition of NK cell suppression of T cell proliferation. Similarly GRAIL overexpression in NK cells induced their regulatory function. HINT1/Hsp70 treatment generated regulatory NK cells characterized by expression of GRAIL.

CD80-IL2 Expressing Myeloma Cells for Immune Gene Therapy of Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4718-4718
Author(s):  
Giulia Giunti ◽  
David Malone ◽  
Lucas Chan ◽  
Darling David ◽  
Shahram Y Kordasti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Cytolytic Activity ◽  
Immune Gene ◽  
Moderate Increase ◽  
Myeloma Cells ◽  
Cell Functions

Abstract Abstract 4718 Improved experimental therapies are needed for Multiple Myeloma (MM). Despite major progress in treatment and initial induction of remission, myeloma remains an incurable disease. Although immunotherapy and, in particular, the employment of NK cells offers an approach of interest for the treatment of Multiple Myeloma (MM), recent studies have shown that myeloma cells utilise a number different mechanisms to impair NK and T cell functions. Important amongst these mechanisms is the reduced expression of CD80 in the sub-populations of PBMC isolated from myeloma patients. We have previously demonstrated CD80/IL-2 mediated stimulation of NK and T cells isolated from AML patients (as measured by proliferation, cytokine release and target cell specific cytolytic activity). In the present study we have examined the ability of genetically modified MM cells engineered to express CD80 and IL-2 to stimulate NK cell functions. These studies confirm the ability of MM cells to suppress NK cell functions in healthy PBMC and show that in contrast to the unmodified MM cells, the CD80/IL-2 expressing MM cells are able to stimulate a moderate increase in NK and T cell numbers and a significant increase in the fraction of NK cells with activatory receptors (NKp44, NKp30, NKp46) and activation markers (CD69) on the cell surface of both NK and T cells. More importantly for potential therapeutic applications the stimulated NK cells show increased cytolytic activity against the unmodified MM cells. This data suggest that CD80/IL-2 MM cells may be able to overcome the immune suppressive functions of unmodified MM cells and to stimulate NK, and T cell mediated responses against the unmodified MM cells. Therefore CD80/IL-2 expressing MM cells may provide a suitable cellular vaccine for NK cell stimulation and possibly the induction of broader ranging immunological responses against multiple myeloma cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High Dose Intravenous IgG Therapy Modulates Multiple NK Cell and T Cell Functions in Patients With Immune Dysregulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Sarah M. McAlpine ◽  
Sarah E. Roberts ◽  
John J. Heath ◽  
Fabian Käsermann ◽  
Andrew C. Issekutz ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Immune Dysregulation ◽  
Ivig Treatment ◽  
High Dose ◽  
Lymphocyte Function ◽  
Resolution Of Inflammation ◽  
Cell Functions

Intravenous immunoglobulin (IVIG) is an effective immunomodulatory treatment for immune dysregulation diseases. However, the mechanisms by which it reduces systemic inflammation are not well understood. NK cell cytotoxicity is decreased by IVIG in women with reduced fertility, but IVIG effects on NK cells in immune dysregulation are less clear. We hypothesized that IVIG modulation of lymphocyte function, especially in NK cells, is important for resolution of inflammation. Our aim was to identify IVIG-induced changes in a cohort of patients with Kawasaki disease (KD) and those that occur broadly in pediatric patients with various immune dysregulatory diseases. Peripheral blood mononuclear cells (PBMCs) of patients with KD or autoimmune/inflammatory diseases were phenotyped pre and post high dose IVIG treatment by flow cytometry. In KD patients, after IVIG infusion Treg cell frequency and the proportion of activated CD25+ immunoregulatory CD56bright NK cells was increased, and multiple lymphocyte subsets showed increased expression of the lymphoid tissue homing receptor CD62L. Importantly, IVIG treatment decreased the frequency of cells expressing the degranulation marker CD107a among cytotoxic CD56dim NK cells, which was reflected in a significant reduction in target cell killing and in decreased production of multiple pro-inflammatory mediators. Interestingly, the activating receptor CD336 was expressed on a higher proportion of CD56bright NK cells after IVIG in both KD and autoimmune/inflammatory patients while other NK receptors were increased differentially in each cohort. In autoimmune/inflammatory patients IVIG induced the proliferation marker CD71 on a higher percentage of CD56dim NK cells, and in contrast to KD patients, CD107a+ cells were increased in this subset. Furthermore, when PBMCs were stimulated ex vivo with IL-2 or Candida antigen in autologous plasma, more of the CD4+ T cells of KD patients expressed CD25 after IVIG therapy but fewer cytotoxic T cells were degranulated based on CD107a expression. In summary, IVIG treatment in patients with immune dysregulation has multiple effects, especially on NK cell subsets and CD4+ T cells, which are compatible with promoting resolution of inflammation. These novel findings provide insight into the immunomodulatory actions of IVIG in autoimmune and inflammatory conditions.

scholarly journals The JAK1 Selective Inhibitor ABT 317 Blocks Signaling Through Interferon-γ and Common γ Chain Cytokine Receptors to Reverse Autoimmune Diabetes in NOD Mice

2020 ◽  
Vol 11 ◽  
Author(s):  
Tingting Ge ◽  
Gaurang Jhala ◽  
Stacey Fynch ◽  
Satoru Akazawa ◽  
Sara Litwak ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Interferon Γ ◽  
Selective Inhibitor ◽  
T Cell Proliferation ◽  
Β Cells ◽  
Ifn Γ

Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8+ T cells in type 1 diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-γ signaling in β cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, ABT 317 reduced CD8+ T cell proliferation as well as the number of KLRG+ effector and CD44hiCD62Llo effector memory CD8+ T cells in spleen. ABT 317 also prevented MHC class I upregulation on β cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFN-γ receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes.

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