scholarly journals HIV-1-induced cytokines deplete homeostatic ILCs and expand TCF7-dependent memory NK cells: Supplemental Figures and Tables

2017 ◽  
Author(s):  
Yetao Wang ◽  
Kyle Gellatly ◽  
Sean McCauley ◽  
Pranitha Vangala ◽  
Kyusik Kim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Inflammatory Cytokines ◽  
Nk Cell ◽  
Ex Vivo ◽  
Developmental Trajectory ◽  
Lymphoid Cells ◽  
Infected People ◽  
Cell Induction ◽  
Hiv 1 ◽  
Memory Nk Cells

HIV-1-infected people who take medications that suppress viremia, preserve CD4+ T cells, and prevent AIDS, have chronic inflammation with increased cardiovascular mortality. To investigate the etiology of this inflammation, the effect of HIV-1 on innate lymphoid cells (ILCs) and NK cells was examined. Homeostatic ILCs in blood and intestine were depleted permanently. NK cells were skewed towards a memory subset. Cytokines that are elevated during HIV-1 infection reproduced both abnormalities ex vivo. Pseudotime analysis of single NK cell transcriptomes revealed a developmental trajectory towards a subset with expression profile, chromatin state, and biological function like memory T lymphocytes. Expression of TCF7, a WNT transcription factor, increased over the course of the trajectory. TCF7 disruption, or WNT inhibition, prevented memory NK cell induction by inflammatory cytokines. These results demonstrate that inflammatory cytokines associated with HIV-1 infection irreversibly disrupt homeostatic ILCs and cause developmental shift towards TCF7+ memory NK cells.

scholarly journals Potential of the NKG2D/NKG2DL Axis in NK Cell-Mediated Clearance of the HIV-1 Reservoir

2019 ◽  
Vol 20 (18) ◽  
pp. 4490 ◽  
Author(s):  
Maria G. Desimio ◽  
Daniela A. Covino ◽  
Margherita Doria
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Virus Reactivation ◽  
Major Drawback ◽  
Virus Eradication ◽  
Latent Hiv ◽  
Hiv 1

Viral persistency in latently infected CD4+ T cells despite antiretroviral therapy (ART) represents a major drawback in the fight against HIV-1. Efforts to purge latent HIV-1 have been attempted using latency reversing agents (LRAs) that activate expression of the quiescent virus. However, initial trials have shown that immune responses of ART-treated patients are ineffective at clearing LRA-reactivated HIV-1 reservoirs, suggesting that an adjuvant immunotherapy is needed. Here we overview multiple lines of evidence indicating that natural killer (NK) cells have the potential to induce anti-HIV-1 responses relevant for virus eradication. In particular, we focus on the role of the NKG2D activating receptor that crucially enables NK cell-mediated killing of HIV-1-infected cells. We describe recent data indicating that LRAs can synergize with HIV-1 at upregulating ligands for NKG2D (NKG2DLs), hence sensitizing T cells that exit from viral latency for recognition and lysis by NK cells; in addition, we report in vivo and ex vivo data showing the potential benefits and drawbacks that LRAs may have on NKG2D expression and, more in general, on the cytotoxicity of NK cells. Finally, we discuss how the NKG2D/NKG2DLs axis can be exploited for the development of effective HIV-1 eradication strategies combining LRA-induced virus reactivation with recently optimized NK cell-based immunotherapies.

scholarly journals HIV-1-induced cytokines deplete homeostatic innate lymphoid cells and expand TCF7-dependent memory NK cells

2020 ◽  
Vol 21 (3) ◽  
pp. 274-286 ◽  
Author(s):  
Yetao Wang ◽  
Lawrence Lifshitz ◽  
Kyle Gellatly ◽  
Carol L. Vinton ◽  
Kathleen Busman-Sahay ◽  
...  
Keyword(s):  
Nk Cells ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Hiv 1 ◽  
Memory Nk Cells

scholarly journals The Effect of Antiretroviral Naïve HIV-1 Infection on the Ability of Natural Killer Cells to Produce IFN-γ upon Exposure to Plasmodium falciparum-Infected Erythrocytes

2017 ◽  
Vol 2 (1) ◽  
pp. 1-13
Author(s):  
Carole Stéphanie Sake ◽  
Loveline Ngu ◽  
Georgia Ambada ◽  
Jean Paul Chedjou ◽  
Nadesh Nji ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Plasmodium Species ◽  
Sub Saharan Africa ◽  
Cell Mediated Immunity ◽  
Infected People ◽  
Ifn Γ ◽  
Hiv 1

Background: In sub-Saharan Africa, intense perennial Plasmodium species transmission coincides with areas of high prevalence of the human immunodeficiency virus type 1 (HIV) infection. This implies that antiretroviral naïve HIV-infected people living within these regions are repeatedly exposed to Plasmodium species infection and consequently malaria. Natural killer (NK) cells are known to contribute to malaria immunity through the production of IFN-γ after exposure to Plasmodium falciparum-infected erythrocytes (infected red blood cells [iRBC]). However, in antiretroviral naïve HIV-1 infection, these functions could be impaired. In this study we assess the ability of NK cells from antiretroviral naïve HIV-1-infected people to respond to iRBC. Method: Magnetically sorted NK cells from antiretroviral naïve HIV-1-infected people were tested for their ability to respond to iRBC following in vitro coculture. NK cell IFN-γ production after coculture was measured through multiparametric flow cytometry analysis. Results: Our data show a significant reduction (p = 0.03) in IFN-γ production by NK cells from antiretroviral naïve HIV-1-infected people after coculture with iRBCs. This was in contrast to the NK cell response from healthy controls, which demonstrated elevated IFN-γ production. NK cell IFN-γ production from untreated HIV-1-infected participants correlated inversely with the viral load (r = -0.5, p = 0.02) and positively with total helper CD4+ T-cell count (r = 0.4, p = 0.04). Thus, antiretroviral naïve HIV-1 infection can dampen NK cell-mediated immunity to P. falciparum infection in malaria-intense regions. This could in effect escalate morbidity and mortality in people chronically infected with HIV-1.

scholarly journals Human antigen-specific memory natural killer cell responses develop against HIV-1 and influenza virus and are dependent on MHC-E restriction

2020 ◽  
Author(s):  
Stephanie Jost ◽  
Olivier Lucar ◽  
Taylor Yoder ◽  
Kyle Kroll ◽  
Sho Sugawara ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Health Priorities ◽  
Antigen Specificity ◽  
Cell Memory ◽  
Specific Memory ◽  
Hiv 1 ◽  
Memory Nk Cells

ABSTRACTFor over a decade, multiple studies have disputed the notion of natural killer (NK) cells as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including two critical global health priorities – HIV and influenza. However, the mechanisms underlying antigen specificity remain unknown. Herein, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism firmly dependent on the activating CD94/NKG2C receptor and its ligand HLA-E, and confirm these findings by three rigorous and novel assays. We validated the permanent acquisition of antigen-specificity by individual memory NK cells by single-cell cloning. We identified biomarkers of antigen-specific NK cell memory through RNA-Seq transcriptomic fingerprints and complex immunophenotyping by 30-parameter flow cytometry showing elevated expression of KLRG1, α4β7 and NKG2C. Finally, we show individual HLA-E-restricted peptides that may constitute the dominant response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms behind formation of antigen-specific memory NK cells, and suggest they could be targeted for future vaccines, cure strategies, or other therapeutic interventions.

scholarly journals CD200R1 Distinguishes Uncommitted Precursors from Functionally Mature NK Cells within the Human Tonsil Stage 4A NK Cell Population

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 993-993
Author(s):  
Youssef Youssef ◽  
Ansel P. Nalin ◽  
Jesse Kowalski ◽  
Megan Broughton ◽  
Matthew Lordo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Single Cell ◽  
Cell Population ◽  
Nk Cell ◽  
Ex Vivo ◽  
Cell Subset ◽  
Cell Development ◽  
Lymphoid Cells ◽  
Lymphoid Tissues ◽  
Human Tonsil

Abstract Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) whose development and anti-tumor functions can be critical for the successful treatment and long-term disease-free survival of patients with hematologic malignancies. In humans, NK cells derive from bone marrow resident hematopoietic progenitor cells that traffic to secondary lymphoid tissues (SLTs) where they complete their terminal differentiation and maturation through a series of developmental stages before returning to the blood as mature NK cells. Although major stages of human NK cell development in SLTs have been clearly defined according to the differential surface expression of CD34, CD117, CD94, NKp80, CD16, and CD57 among lineage antigen (Lin) negative lymphocytes, continued investigation has revealed additional phenotypic and functional heterogeneity at each developmental stage. Through extensive ex vivo single-cell RNA sequencing and flow cytometry analyses we have identified two subsets of tonsil-resident Lin -CD34 -CD117 +/-CD94 +NKp80 -CD16 -CD57 - stage 4A NK cells. These two subsets differ in their expression of the inhibitory receptor, CD200R1, which is not expressed by mature NK cells in the peripheral blood from healthy individuals. The majority of stage 4A cells expressed high amounts of surface CD200R1, which correlated with low gene and undetectable protein expression of intracellular cytolytic granules (perforin and granzymes A, B, K, and M), killer immunoglobulin-like receptors (KIRs), and transcription factors required for terminal NK cell maturation (EOMES, T-BET). In addition, upon ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, CD200R1 + stage 4A NKDIs did not produce interferon-gamma (IFN-g), a hallmark feature of mature NK cells. In contrast, many CD200R1 - stage 4A cells constitutively expressed perforin, granzymes, EOMES, and/or T-BET; many expressed KIRs; and many produced IFN-g upon ex vivo stimulation. Furthermore, the frequency of KIR + cells among CD200R1 - stage 4A cells was significantly higher than that among autologous tonsil stage 4B NK cells (Lin -CD34 -CD117 +/-CD94 +NKp80 +CD16 -CD57 -) (20.8 ± 1.65 vs. 8.12 ± 1.66; p < 0.01; n = 14), suggesting that as a population CD200R1 - stage 4A cells are potentially out of sequence in terms of the linear NK cell developmental pathway. Based on these ex vivo findings, we hypothesized that CD200R1 + stage 4A cells represent NK cell precursors, whereas the CD200R1 - stage 4A population contains more mature NK cells that lack NKp80, CD16, and CD57. To further address this hypothesis and to determine their ex vivo potentials for NK cell and non-NK ILC differentiation, we cultured CD200R1 + and CD200R1 - stage 4A cells in vitro in the presence of OP9-DL1 stroma and recombinant human IL-7 and IL-15, conditions previously shown to support all human ILC and NK cell subset differentiation. Under these conditions, both stage 4A populations generated NKp80 + NK cells in bulk and single-cell clonal assays, whereas neither population gave rise to ILC2s (CD294 +) which precede stage 4A NK cells in the developmental scheme. However, while the majority of cultures derived from CD200R1 + stage 4A clones contained ILC3s (CD94 -NKp44 +), significantly fewer clones from CD200R1 - stage 4A cells produced ILC3s (7 of 26 CD200R1 - clones vs. 20 of 23 CD200R1 + clones; p = 0.000587). Moreover, none of the CD200R1 - stage 4A-derived clonal cultures that contained KIR + NK cells contained ILC3s, suggesting that the majority of CD200R1 - stage 4A cells are lineage committed NK cells. Collectively, these data further characterize the heterogeneity of the human tonsil stage 4A NK cell population and identify CD200R1 as a marker distinguishing uncommitted precursor cells from a minor population of cells with otherwise mature NK-associated phenotype and function. In light of the role of CD200R1 in regulating lymphocyte functions in the setting of cancer, further research is warranted to determine its potential role(s) in regulating human NK cell development. Disclosures Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria.

scholarly journals TLR1/2 Agonist Enhances Reversal of HIV-1 Latency and Promotes NK Cell-Induced Suppression of HIV-1-Infected Autologous CD4 + T Cells

2021 ◽  
Author(s):  
Siqin Duan ◽  
Xinfeng Xu ◽  
Jinshen Wang ◽  
Liwen Huang ◽  
Jie Peng ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Shock And Kill ◽  
Infected Cells ◽  
Hiv 1

The complete eradication of human immunodeficiency virus type 1 (HIV-1) is blocked by latent reservoirs in CD4 + T cells and myeloid lineage cells. Toll-like receptors (TLRs) can induce the reversal of HIV-1 latency and trigger the innate immune response. To the best of our knowledge, there is little evidence show the “killing” effect of TLR1/2 agonists but only with a small “shock” potential. To identify a new approach for eradicating the HIV latent reservoir, we evaluated the effectiveness of SMU-Z1, a novel TLR1/2 small molecule agonist, in the “shock and kill” strategy. The results showed that SMU-Z1 can not only enhance latent HIV-1 transcription in ex vivo peripheral blood mononuclear cells (PBMCs) from aviremic HIV-1-infected donors receiving combined antiretroviral therapy (cART) but also in cells of myeloid-monocytic origin in vitro targeting the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Interestingly, activation marker CD69 was significantly upregulated in NK cells, B cells, and monocytes 48 hours after SMU-Z1 treatment. Furthermore, SMU-Z1 was able to activate T cells without global T cell activation, as well as increase NK cell degranulation and interferon-gamma (IFN-γ) production which further block HIV-1-infected CD4 lymphocytes. In summary, the present study found that SMU-Z1 can both enhance HIV-1 transcription and promote NK cell-mediated inhibition of HIV-1-infected autologous CD4 + T cells. These findings indicate that novel TLR1/2 agonist SMU-Z1 is a promising latency-reversing agent (LRA) for eradication of HIV-1 reservoirs. IMPORTANCE Multiple in vivo studies have shown that many LRAs implemented in the “shock and kill” approach could activate viral transcription but could not induce “killing” effectively. Therefore, a dual function LRA is needed for elimination of HIV-1 reservoirs. We previously developed a small molecule TLR1/2 agonist, SMU-Z1, and demonstrated that it could upregulate NK cells and CD8 + T cells with immune adjuvant and anti-tumor properties in vivo . In the present study, SMU-Z1 can activate innate immune cells without global T cell activation, induce production of proinflammatory and antiviral cytokines, and enhance the cytotoxic function of NK cells. We showed that SMU-Z1 displayed dual potential ex vivo in the “shock” of exposure of HIV-1 latently infected cells and in the “kill” of clearance of infected cells, which is critical for effective use in combination with therapeutic vaccines or broadly neutralizing antibody treatments aimed at curing AIDS.

scholarly journals Decrease post-transplant relapse using donor-derived expanded NK-cells

Leukemia ◽  
2021 ◽  
Author(s):  
Stefan O. Ciurea ◽  
Piyanuch Kongtim ◽  
Doris Soebbing ◽  
Prashant Trikha ◽  
Gregory Behbehani ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Disease Free Survival ◽  
Dependent Manner ◽  
Post Transplant ◽  
Haploidentical Transplantation ◽  
High Doses ◽  
High Level

AbstractIn this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105–1 × 108 cells/kg/dose) were administered on days −2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 (https://clinicaltrials.gov/ct2/show/NCT01904136).

scholarly journals Role and Modulation of NK Cells in Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 167-181
Author(s):  
Marie Thérèse Rubio ◽  
Adèle Dhuyser ◽  
Stéphanie Nguyen
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Proteasome Inhibitors ◽  
Disease Evolution ◽  
Cell Functions

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.

scholarly journals Immunosenescence of Natural Killer Cells, Inflammation, and Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Corona Solana ◽  
Raquel Tarazona ◽  
Rafael Solana
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Neurodegenerative Disorder ◽  
The Elderly ◽  
Lymphoid Cells ◽  
Target Cells ◽  
The Brain

Alzheimer’s disease (AD) represents the most common cause of dementia in the elderly. AD is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although the aetiology of AD is not clear, both environmental factors and heritable predisposition may contribute to disease occurrence. In addition, inflammation and immune system alterations have been linked to AD. The prevailing hypothesis as cause of AD is the deposition in the brain of amyloid beta peptides (Aβ). Although Aβ have a role in defending the brain against infections, their accumulation promotes an inflammatory response mediated by microglia and astrocytes. The production of proinflammatory cytokines and other inflammatory mediators such as prostaglandins and complement factors favours the recruitment of peripheral immune cells further promoting neuroinflammation. Age-related inflammation and chronic infection with herpes virus such as cytomegalovirus may also contribute to inflammation in AD patients. Natural killer (NK) cells are innate lymphoid cells involved in host defence against viral infections and tumours. Once activated NK cells secrete cytokines such as IFN-γ and TNF-α and chemokines and exert cytotoxic activity against target cells. In the elderly, changes in NK cell compartment have been described which may contribute to the lower capacity of elderly individuals to respond to pathogens and tumours. Recently, the role of NK cells in the immunopathogenesis of AD is discussed. Although in AD patients the frequency of NK cells is not affected, a high NK cell response to cytokines has been described together with NK cell dysregulation of signalling pathways which is in part involved in this altered behaviour.

scholarly journals Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Abena K. R. Kwaa ◽  
Chloe A. G. Talana ◽  
Joel N. Blankson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Effector Cell ◽  
Cell Function ◽  
Nk Cell ◽  
Suppressive Capacity ◽  
Short Course ◽  
Shock And Kill ◽  
Hiv 1

ABSTRACTCurrent shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

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