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.

Activation of NK Cells Induces CD4 Expression and Allows HIV−1 Infection.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1253-1253
Author(s):  
Hideki Harada ◽  
Yumi Goto ◽  
Omar F. Dessouki ◽  
Shinya Suzu ◽  
Seiji Okada
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Number ◽  
Cell Contact ◽  
Specific Marker ◽  
Activation Markers ◽  
Hiv 1

Abstract Natural killer (NK) cells play critical roles in immune surveillance without deliberate prior sensitization and restriction by major histocompatibility complex (MHC). Although function and cell number of NK cells are influenced in AIDS patients, direct interaction between HIV and NK cells is still controversial. Because steady-state NK cells are negative for CD4 which is a key molecule for HIV infection. In this study, we established a condition inducing CD4 expression and HIV-1 infection of NK cells in vitro. CD4 was expressed on NK cells co-cultured with HFWT cells (NK cell-selective stimulating feeder cells) and IL-2. There were no differences in expression level of NK receptors, adhesion molecules and cytotoxicity between CD4+ and CD4- NK cell subpopulations. However, expression of activation markers, CD25 and HLA-DR, and size/granularity of the CD4+ NK cells were higher than CD4- NK cells. CD4+ NK cells expressed co-receptors for HIV-1, CCR5 and CXCR4. Thus, CD4 is induced on NK cells by activation, and the CD4+ NK cells are the possible target for HIV. Next, we exposed HIV-1 clone (JR-FL) to the HFWT-activated NK cells, however, direct HIV infection to the NK cells was not observed. While, co-culture of activated NK cells with HIV infected T cells allowed HIV infection of NK cells. Because NK cell-specific marker, NKp46, was detected on p24+CD3-CD56+ cells but not on CD3+ cells, p24+CD3-CD56+ cells were certainly NK cells. These results demonstrate that NK cells are the targets of HIV. Altogether, our data suggest that CD4+ T cells transfer HIV to NK cells during this cell-to-cell contact, which cause the NK cells to be the long-living viral reservoirs or modify the function of NK cells in HIV-infected patients. Our novel co-culture system using activated NK cells and HIV-infected T cells is the powerful tool to study the function of NK cells on HIV infection.

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.

scholarly journals Endothelial cells promote productive HIV infection of resting CD4+ T cells by an integrin-mediated cell adhesion-dependent mechanism

2020 ◽  
Author(s):  
Catherine M. Card ◽  
Bernard Abrenica ◽  
Lyle R. McKinnon ◽  
T. Blake Ball ◽  
Ruey-Chyi Su
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Cell Trafficking ◽  
Hiv Replication ◽  
Hiv Susceptibility ◽  
Hiv Acquisition ◽  
Memory Cd4 T Cells

AbstractResting CD4+ T cells do not support HIV replication in vitro, yet are primary targets of early HIV infection events in vivo. There is an established role for factors in the tissue microenvironment, including endothelial cells, in enhancing the susceptibility of resting CD4+ T cells to productive infection, yet the mechanisms behind this are not well understood. Endothelial cells facilitate immune cell trafficking throughout the body. Cell adhesion molecules expressed by endothelial cells engage integrins on activated and memory T cells and mediate transmigration into inflamed tissues. These cell trafficking pathways have overlapping roles in facilitating HIV replication but their relevance to endothelial cell-mediated enhancement of HIV susceptibility in resting CD4+ T cells has not previously been examined. We used flow cytometry to characterize the phenotype resting CD4+ T cells that became productively infected when exposed to HIV in the presence of endothelial cells. Infected CD4+ T cells were primarily central memory cells enriched for high expression of the integrins LFA-1 and VLA-4 and had variable expression of α4β7, CCR6 and CD69. Blocking LFA-1 and VLA-4 on resting CD4+ T cells abrogated infection in the co-culture model, indicating that engagement of these integrins is essential for enhancement of resting CD4+ T cell HIV susceptibility by endothelial cells. Cellular activation of CD4+ T cells did not appear to be the primary mechanism enabling HIV replication since only a small proportion of resting CD4+ T cells became activated over the course of the co-culture and fewer than half of infected cells had an activated phenotype. The demonstration that endothelial cells enhance the cellular HIV susceptibility of resting memory CD4+ T cells through cell trafficking pathways engaged during the transmigration of memory T cells into inflamed tissues highlights the physiological relevance of these findings for HIV acquisition and opportunities for intervention.Author SummaryHIV acquisition risk per coital act is relatively low, but this risk is amplified by various behavioural and biological variables. Genital inflammation is a key biological variable associated with increased risk of HIV acquisition, but the mechanisms driving this are incompletely understood. Inflammation is a complex process, with direct effects on HIV target cells as well as the tissue in which those cells reside and encounter virus. The first HIV target cells in vivo are resting memory CD4+ T cells, yet these cells are do not support viral replication when purified and exposed to HIV in vitro. Rather, signals from tissue microenvironment are required to support viral replication within resting memory CD4+ T cells. Endothelial cells line tissue vasculature and guide immune cell trafficking to inflamed tissues through engagement of integrins by endothelial-expressed cell adhesion molecules. We show here that these same cell-trafficking pathways enable endothelial cells to promote HIV replication within resting memory CD4+ T cells in vitro. Blockade of integrins on resting memory CD4+ T cells prevented endothelial enhancement of HIV infection. These findings further our understanding of the determinants of cellular susceptibility to HIV infection and offer a potential mechanism by which inflammation promotes HIV acquisition.

scholarly journals Enhancing natural killer cell function with gp41-targeting bispecific antibodies to combat HIV infection

2019 ◽  
Author(s):  
Nitya S. Ramadoss ◽  
Nancy Q. Zhao ◽  
Barbra A. Richardson ◽  
Philip M. Grant ◽  
Peter S. Kim ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Bispecific Antibodies ◽  
Target Cells ◽  
Infected Cells

AbstractObjective(s)To develop and evaluate the activity of bispecific antibodies (bsAbs) to enhance NK cell antibody-dependent cellular cytotoxicity (ADCC) against HIV-infected cells.DesignThese bsAbs are based on patient-derived antibodies targeting the conserved gp41 stump of HIV Env, and also incorporate a high affinity scFv targeting the activating receptor CD16 on NK cells. Overall, we expect the bsAbs to provide increased affinity and avidity over their corresponding monoclonal antibodies, allowing for improved ADCC activity against Env-expressing target cells.MethodsbsAbs and their corresponding mAbs were expressed in 293T cells and purified. The binding of bsAbs and mAbs to their intended targets was determined using Bio-Layer Interferometry, as well as flow cytometry-based binding assays on in vitro infected cells. The ability of these bsAbs to improve NK cell activity against HIV-infected cells was tested using in vitro co-culture assays, using flow cytometry and calcein release to analyze NK cell degranulation and target cell killing, respectively.ResultsThe bsAbs bound gp41 with similar affinity to their corresponding mAbs, and had increased affinity for CD16. The bsAbs also bound to primary CD4 T cells infected in vitro with two different strains of HIV. In addition, the bsAbs induce increased NK cell degranulation and killing of autologous HIV-infected CD4 T cells.ConclusionsThese bsAbs may provide a promising strategy to improve NK-mediated immune targeting of infected cells during HIV infection.

scholarly journals Quantity and Quality Reconstitution of NKG2A+ NK Cells Are Associated with Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4582-4582
Author(s):  
Lijuan Hu ◽  
Xiang-Yu Zhao ◽  
Xingxing Yu ◽  
Meng Lv ◽  
Ting-Ting Han ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Nk Cell ◽  
Graft Versus Host ◽  
Cell Counts ◽  
Alloreactive T Cells

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment strategy for hematological malignancies. However, graft-versus-host disease (GVHD) is a common complication after allo-HSCT resulting from the activation, amplification and secretion of numerous inflammatory factors related to donor alloreactive T cells that damage host tissues and organs, mainly in the gastrointestinal tract, liver and skin. Notably, natural killer (NK) cells represent the first donor-derived lymphocyte population to recover after allo-HSCT and generally are observed within the first month after allo-HSCT. NK cells express a series of immune receptors that identify relevant ligands on target cells and maintain the immune balance between NK cell activation and tolerance. Previous studies have shown that the number of NKG2A+ cells is decreased in patients with chronic GHVD after HSCT. However, the relationship between NKG2A+ NK cells and aGVHD has not been characterized. In addition, the role of NKG2A+ cells in aGVHD disease progression and the mechanism underlying NKG2A+ cell immunoregulation have not been clearly explained. Objective: In this study, we used peripheral blood from GVHD, non-GVHD paired specimens and healthy donors to address the underlying mechanism by which NKG2A+ NK cells regulate T cells after HSCT. Methods: We detected the specimens using flow cytometry from two independent cohorts, which were prospective cohort and paired cohort. Futher, we performed experiments in vitro to investigate the potential role of NKG2A+ NK cells on T cells. Results: Here, we found that, compared with non-GVHD subset, NKG2A+ NK cells percentage and absolute cell counts were significantly reduced in GVHD patients after HSCT. Moreover, the reduction of NKG2A+ NK cells in GVHD patients was ascribed to its increased apoptosis and decreased proliferation capacity, while retaining a strong graft-versus-leukemia (GVL) effect. In vitro assay showed that when co-cultured T cells with NKG2A+ NK cells, the T cells secreted IFN-r level was significantly reduced, while the IL-4 level was increased. Moreover, CD25 expression level was decreased, while the CD4+CD25+FOXP3+ cells number was increased. In addition, the NKG2A+ NK cells induced T cell apoptosis and decreased T cell proliferation during the coculture process. Significantly, NKG2A+ mainly regulated activated but not resting T cells. In vivo assay showed that serological IL-10 level in GVHD subset was evidently lower than those of non-GVHD subgroup, the IL-1β, IFN-r and TNF-a level was however higher in the GVHD subgroup. Furthermore, the percentage of NKG2A+ NK cells from GVHD patients was markedly increased by the presence of exogenous IL-10, but not by other cytokines. However, this phenotype was not observed at non-GVHD patients. Together, the GVHD might be ascribed to lower IL-10 induced NKG2A+ NK cells reduction, which further overactivate T cells after HSCT. Discussion and Conclusion: Overall, we herein observed reduced proportions and absolute cell counts of NK cells and NKG2A+ subsets in patients with acute GVHD after allo-HSCT. The causative association between NK cell numbers, NKG2A+ subsets and GVHD remains debatable. Based on our results, speculating that reduced proportions of NKG2A+ subsets in patients after allo-HSCT are associated with acute GVHD due to their interplay with the patient's donor-derived alloreactive T cells is tempting. Disclosures No relevant conflicts of interest to declare.

scholarly journals Sustained effector function of IL-12/15/18–preactivated NK cells against established tumors

2012 ◽  
Vol 209 (13) ◽  
pp. 2351-2365 ◽  
Author(s):  
Jing Ni ◽  
Matthias Miller ◽  
Ana Stojanovic ◽  
Natalio Garbi ◽  
Adelheid Cerwenka
Keyword(s):  
T Cells ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Rational Design ◽  
Nk Cell ◽  
Killer Cell ◽  
Effector Function

Natural killer cell (NK cell)–based immunotherapy of cancer is hampered by the transient effector function of NK cells. Recently, mouse IL-12/15/18–preactivated NK cells were shown to persist with sustained effector function in vivo. Our study investigated the antitumor activity of such NK cells. A single injection of syngeneic IL-12/15/18–preactivated NK cells, but neither naive nor IL-15– or IL-2–pretreated NK cells, combined with irradiation substantially reduced growth of established mouse tumors. Radiation therapy (RT) was essential for the antitumor activity of transferred NK cells. IL-12/15/18–preactivated NK cells expressed high levels of IL-2Rα (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18–preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells. RT greatly increased numbers and function of transferred NK cells. Human IL-12/15/18–preactivated NK cells also displayed sustained effector function in vitro. Our study provides a better understanding for the rational design of immunotherapies of cancer that incorporate NK cells. Moreover, our results reveal an essential role of CD4+ T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.

scholarly journals Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo

2009 ◽  
Vol 206 (13) ◽  
pp. 2977-2986 ◽  
Author(s):  
Shintaro Kamizono ◽  
Gordon S. Duncan ◽  
Markus G. Seidel ◽  
Akira Morimoto ◽  
Koichi Hamada ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Leucine Zipper ◽  
Nk Cell ◽  
Interferon Γ ◽  
Cytolytic Activity ◽  
Nk T Cells

Nuclear factor interleukin-3 (Nfil3; also known as E4-binding protein 4) is a basic region leucine zipper transcription factor that has antiapoptotic activity in vitro under conditions of growth factor withdrawal. To study the role of Nfil3 in vivo, we generated gene-targeted Nfil3-deficient (Nfil3−/−) mice. Nfil3−/− mice were born at normal Mendelian frequency and were grossly normal and fertile. Although numbers of T cells, B cells, and natural killer (NK) T cells were normal in Nfil3−/− mice, a specific disruption in NK cell development resulted in severely reduced numbers of mature NK cells in the periphery. This defect was NK cell intrinsic in nature, leading to a failure to reject MHC class I–deficient cells in vivo and reductions in both interferon γ production and cytolytic activity in vitro. Our results confirm the specific and essential requirement of Nfil3 for the development of cells of the NK lineage.

scholarly journals Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

2021 ◽  
Vol 7 (8) ◽  
pp. eabc2331 ◽  
Author(s):  
Jose M. Ayuso ◽  
Shujah Rehman ◽  
Maria Virumbrales-Munoz ◽  
Patrick H. McMinn ◽  
Peter Geiger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Waste Product ◽  
Extended Period ◽  
Cell Exhaustion

Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model

2020 ◽  
Vol 69 (1) ◽  
pp. 28-40 ◽  
Author(s):  
Ross Cromarty ◽  
Alexander Sigal ◽  
Lenine Julie Liebenberg ◽  
Lyle Robert Mckinnon ◽  
Salim Safurdeen Abdool Karim ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Immune Activation ◽  
Cd4 T Cells ◽  
Drug Targets ◽  
Complex Nature ◽  
Peripheral Blood Mononuclear ◽  
Established Risk Factor ◽  
Anti Inflammatory

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.

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