scholarly journals Monkeying around with MAIT Cells: Studying the Role of MAIT Cells in SIV and Mtb Co-Infection

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 863
Author(s):  
Ryan V. Moriarty ◽  
Amy L. Ellis ◽  
Shelby L. O’Connor
Keyword(s):  
Cell Function ◽  
Current Knowledge ◽  
Cell Activity ◽  
Cell Dynamics ◽  
Tissue Samples ◽  
Mait Cells ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Infected Cells ◽  
Mait Cell

There were an estimated 10 million new cases of tuberculosis (TB) disease in 2019. While over 90% of individuals successfully control Mycobacterium tuberculosis (Mtb) infection, which causes TB disease, HIV co-infection often leads to active TB disease. Despite the co-endemic nature of HIV and TB, knowledge of the immune mechanisms contributing to the loss of control of Mtb replication during HIV infection is lacking. Mucosal-associated invariant T (MAIT) cells are innate-like T cells that target and destroy bacterially-infected cells and may contribute to the control of Mtb infection. Studies examining MAIT cells in human Mtb infection are commonly performed using peripheral blood samples. However, because Mtb infection occurs primarily in lung tissue and lung-associated lymph nodes, these studies may not be fully translatable to the tissues. Additionally, studies longitudinally examining MAIT cell dynamics during HIV/Mtb co-infection are rare, and lung and lymph node tissue samples from HIV+ patients are typically unavailable. Nonhuman primates (NHP) provide a model system to characterize MAIT cell activity during Mtb infection, both in Simian Immunodeficiency Virus (SIV)-infected and SIV-naïve animals. Using NHPs allows for a more comprehensive understanding of tissue-based MAIT cell dynamics during infection with both pathogens. NHP SIV and Mtb infection is similar to human HIV and Mtb infection, and MAIT cells are phenotypically similar in humans and NHPs. Here, we discuss current knowledge surrounding MAIT cells in SIV and Mtb infection, how SIV infection impairs MAIT cell function during Mtb co-infection, and knowledge gaps to address.

scholarly journals Natural Killer Cells in the Malignant Niche of Multiple Myeloma

2022 ◽  
Vol 12 ◽  
Author(s):  
Ondrej Venglar ◽  
Julio Rodriguez Bago ◽  
Benjamin Motais ◽  
Roman Hajek ◽  
Tomas Jelinek
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Natural Killer ◽  
Defense Mechanisms ◽  
Hematological Malignancies ◽  
Cell Function ◽  
Nk Cell ◽  
Current Knowledge ◽  
Suppressor Activity ◽  
Infected Cells

Natural killer (NK) cells represent a subset of CD3- CD7+ CD56+/dim lymphocytes with cytotoxic and suppressor activity against virus-infected cells and cancer cells. The overall potential of NK cells has brought them to the spotlight of targeted immunotherapy in solid and hematological malignancies, including multiple myeloma (MM). Nonetheless, NK cells are subjected to a variety of cancer defense mechanisms, leading to impaired maturation, chemotaxis, target recognition, and killing. This review aims to summarize the available and most current knowledge about cancer-related impairment of NK cell function occurring in MM.

scholarly journals Polyclonal Mucosa-Associated Invariant T Cells Have Unique Innate Functions in Bacterial Infection

2012 ◽  
Vol 80 (9) ◽  
pp. 3256-3267 ◽  
Author(s):  
Wei-Jen Chua ◽  
Steven M. Truscott ◽  
Christopher S. Eickhoff ◽  
Azra Blazevic ◽  
Daniel F. Hoft ◽  
...  
Keyword(s):  
T Cells ◽  
Bacterial Infection ◽  
Cell Function ◽  
Interleukin 12 ◽  
Minor Role ◽  
Microbial Infection ◽  
Bacterial Strains ◽  
Unique Role ◽  
Mait Cells ◽  
Mait Cell

ABSTRACTMucosa-associated invariant T (MAIT) cells are a unique population of αβ T cells in mammals that reside preferentially in mucosal tissues and express an invariant Vα paired with limited Vβ T-cell receptor (TCR) chains. Furthermore, MAIT cell development is dependent upon the expression of the evolutionarily conserved major histocompatibility complex (MHC) class Ib molecule MR1. Usingin vitroassays, recent studies have shown that mouse and human MAIT cells are activated by antigen-presenting cells (APCs) infected with diverse microbes, including numerous bacterial strains and yeasts, but not viral pathogens. However, whether MAIT cells play an important, and perhaps unique, role in controlling microbial infection has remained unclear. To probe MAIT cell function, we show here that purified polyclonal MAIT cells potently inhibit intracellular bacterial growth ofMycobacterium bovisBCG in macrophages (MΦ) in coculture assays, and this inhibitory activity was dependent upon MAIT cell selection by MR1, secretion of gamma interferon (IFN-γ), and an innate interleukin 12 (IL-12) signal from infected MΦ. Surprisingly, however, the cognate recognition of MR1 by MAIT cells on the infected MΦ was found to play only a minor role in MAIT cell effector function. We also report that MAIT cell-deficient mice had higher bacterial loads at early times after infection compared to wild-type (WT) mice, demonstrating that MAIT cells play a unique role among innate lymphocytes in protective immunity against bacterial infection.

scholarly journals MAIT cells are minimally responsive to Mycobacterium tuberculosis within granulomas, but are functionally impaired by SIV in a macaque model of SIV and Mtb co-infection

2020 ◽  
Author(s):  
Amy L. Ellis-Connell ◽  
Alexis J. Balgeman ◽  
Erica C. Larson ◽  
Mark A. Rodgers ◽  
Cassaundra Ameel ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cell Activation ◽  
Cell Function ◽  
Ex Vivo ◽  
Cynomolgus Macaque ◽  
Cross Sectional ◽  
In Vivo Models ◽  
Mait Cells ◽  
Mait Cell

ABSTRACTMucosal associated invariant T (MAIT) cells recognize and can directly destroy bacterially infected cells. While a role for MAIT cells has been suggested in several in vitro and in vivo models of M.tuberculosis (Mtb) infection, these studies have often focused on MAIT cells within the peripheral blood or are cross-sectional studies rather than longitudinal studies. The role of MAIT cells within granulomas and other sites of Mtb infection is relatively unknown. Furthermore, how HIV/SIV infection might impair MAIT cells at the sites of Mtb infection has not been determined. Using a Mauritian cynomolgus macaque (MCM) model system, we phenotyped MAIT cells in the peripheral blood and BAL prior to and during infection with SIVmac239. To characterize the role of MAIT cells within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb for 6 weeks. MAIT cell frequency and function was examined within the peripheral blood, distal airways, as well as within Mtb-affected lymph nodes (LN) and tissues. Surprisingly, we found no evidence of MAIT cell responsiveness to Mtb within granulomas. Additionally, MAIT cells only minimally responded to mycobacterial stimulus in ex vivo functional assays. In contrast, most MAIT cell activation seemed to occur in samples with highly active SIV replication, including blood and SIV-infected LN. Finally, the ability of MAIT cells to secrete TNFα (TNF) was impaired during SIV and Mtb co-infection, indicating that the two pathogens together could have a synergistically deleterious effect on MAIT cell function. The effect of this functional impairment on overall TB disease burden was unclear, but might be deleterious if MAIT cells are needed to fully activate antimycobacterial immune cells within the granulomas.

scholarly journals nef Gene Is Required for Robust Productive Infection by Simian Immunodeficiency Virus of T-Cell-Rich Paracortex in Lymph Nodes

2003 ◽  
Vol 77 (7) ◽  
pp. 4169-4180 ◽  
Author(s):  
Chie Sugimoto ◽  
Kei Tadakuma ◽  
Isao Otani ◽  
Takashi Moritoyo ◽  
Hirofumi Akari ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Productive Infection ◽  
Lymphoid Tissues ◽  
Double Staining ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Infected Cells ◽  
Sivmac239 Infection

ABSTRACT The pathogenesis of AIDS virus infection in a nonhuman primate AIDS model was studied by comparing plasma viral loads, CD4+ T-cell subpopulations in peripheral blood mononuclear cells, and simian immunodeficiency virus (SIV) infection in lymph nodes for rhesus macaques infected with a pathogenic molecularly cloned SIVmac239 strain and those infected with its nef deletion mutant (Δnef). In agreement with many reports, whereas SIVmac239 infection induced AIDS and depletion of memory CD4+ T cells in 2 to 3 years postinfection (p.i.), Δnef infection did not induce any manifestation associated with AIDS up to 6.5 years p.i. To explore the difference in SIV infection in lymphoid tissues, we biopsied lymph nodes at 2, 8, 72, and 82 weeks p.i. and analyzed them by pathological techniques. Maximal numbers of SIV-infected cells (SIV Gag+, Env+, and RNA+) were detected at 2 weeks p.i. in both the SIVmac239-infected animals and the Δnef-infected animals. In the SIVmac239-infected animals, most of the infected cells were localized in the T-cell-rich paracortex, whereas in the Δnef-infected animals, most were localized in B-cell-rich follicles and in the border region between the paracortex and the follicles. Analyses by double staining of CD68+ macrophages and SIV Gag+ cells and by double staining of CD3+ T cells and SIV Env+ cells revealed that SIV-infected cells were identified as CD4+ T cells in either the SIVmac239 or the Δnef infection. Whereas the many functions of Nef protein were reported from in vitro studies, our finding of SIVmac239 replication in the T-cell-rich paracortex in the lymph nodes supports the reported roles of Nef protein in T-cell activation and enhancement of viral infectivity. Furthermore, the abundance of SIVmac239 infection and the paucity of Δnef infection in the T-cell-rich paracortex accounted for the differences in viral replication and pathogenicity between SIVmac239 and the Δnef mutant. Thus, our in vivo study indicated that the nef gene enhances SIV replication by robust productive infection in memory CD4+ T cells in the T-cell-rich region in lymphoid tissues.

scholarly journals Simian Immunodeficiency Virus-Specific CD8+ T Cells Recognize Vpr- and Rev-Derived Epitopes Early after Infection

2010 ◽  
Vol 84 (20) ◽  
pp. 10907-10912 ◽  
Author(s):  
Jonah B. Sacha ◽  
Matthew B. Buechler ◽  
Laura P. Newman ◽  
Jason Reed ◽  
Lyle T. Wallace ◽  
...  
Keyword(s):  
T Cells ◽  
Simian Immunodeficiency Virus ◽  
De Novo ◽  
Cell Epitope ◽  
Cytolytic Activity ◽  
Peptide Epitopes ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Infected Cells ◽  
Kinetics Of

ABSTRACT The kinetics of CD8+ T cell epitope presentation contribute to the antiviral efficacy of these cells yet remain poorly defined. Here, we demonstrate presentation of virion-derived Vpr peptide epitopes early after viral penetration and prior to presentation of Vif-derived epitopes, which required de novo Vif synthesis. Two Rev epitopes exhibited differential presentation kinetics, with one Rev epitope presented within 1 h of infection. We also demonstrate that cytolytic activity mirrors the recognition kinetics of infected cells. These studies show for the first time that Vpr- and Rev-specific CD8+ T cells recognize and kill simian immunodeficiency virus (SIV)-infected CD4+ T cells early after SIV infection.

scholarly journals Impaired Plasmacytoid Dendritic Cell (PDC)-NK Cell Activity in Viremic Human Immunodeficiency Virus Infection Attributable to Impairments in both PDC and NK Cell Function

2009 ◽  
Vol 83 (21) ◽  
pp. 11175-11187 ◽  
Author(s):  
Sara J. Conry ◽  
Kimberly A. Milkovich ◽  
Nicole L. Yonkers ◽  
Benigno Rodriguez ◽  
Helene B. Bernstein ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Cell Function ◽  
Nk Cell ◽  
Granzyme B ◽  
Plasmacytoid Dendritic Cell ◽  
Cell Activity ◽  
Nk Cell Activity ◽  
Immunodeficiency Virus ◽  
Cell Assays ◽  
Ifn Γ

ABSTRACT Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections impair plasmacytoid dendritic cell (PDC) and natural killer (NK) cell subset numbers and functions, though little is known about PDC-NK cell interactions during these infections. We evaluated PDC-dependent NK cell killing and gamma interferon (IFN-γ) and granzyme B production, using peripheral blood mononuclear cell (PBMC)-based and purified cell assays of samples from HCV- and HIV-infected subjects. CpG-enhanced PBMC killing and IFN-γ and granzyme B activity (dependent on PDC and NK cells) were impaired in viremic HIV infection. In purified PDC-NK cell culture experiments, CpG-enhanced, PDC-dependent NK cell activity was cell contact and IFN-α dependent, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-γ-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-α stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-α receptor expression, though IFN-α receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-α-induced NK cell activity and not to altered IFN-α receptor, NKP30, NKP44, NKP46, or NKG2D expression.

scholarly journals Mucosa-Associated Invariant T Cells Are Systemically Depleted in Simian Immunodeficiency Virus-Infected Rhesus Macaques

2016 ◽  
Vol 90 (9) ◽  
pp. 4520-4529 ◽  
Author(s):  
Carol Vinton ◽  
Fan Wu ◽  
Jamie Rossjohn ◽  
Kenta Matsuda ◽  
James McCluskey ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Peripheral Blood ◽  
Opportunistic Infections ◽  
Rhesus Macaques ◽  
Disease Process ◽  
Mesenteric Lymph Nodes ◽  
Mait Cells ◽  
Wide Range ◽  
Immunodeficiency Virus ◽  
Mait Cell

ABSTRACTMucosa-associated invariant T (MAIT) cells contribute to host immune protection against a wide range of potential pathogens via the recognition of bacterial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although bacterial products translocate systemically in human immunodeficiency virus (HIV)-infected individuals and simian immunodeficiency virus (SIV)-infected Asian macaques, several studies have shown that MAIT cell frequencies actually decrease in peripheral blood during the course of HIV/SIV disease. However, the mechanisms underlying this proportional decline remain unclear. In this study, we characterized the phenotype, activation status, functionality, distribution, and clonotypic structure of MAIT cell populations in the peripheral blood, liver, mesenteric lymph nodes (MLNs), jejunum, and bronchoalveolar lavage (BAL) fluid of healthy and SIV-infected rhesus macaques (RMs). Low frequencies of MAIT cells were observed in the peripheral blood, MLNs, and BAL fluid of SIV-infected RMs. These numerical changes were coupled with increased proliferation and a highly public T cell receptor alpha (TCRα) repertoire in the MAIT cell compartment without redistribution to other anatomical sites. Collectively, our data show systemically decreased frequencies of MAIT cells likely attributable to enhanced turnover in SIV-infected RMs. This process may impair protective immunity against certain opportunistic infections with progression to AIDS.IMPORTANCEThe data presented in this study reveal for the first time that MAIT cells are systemically depleted in an AIDS virus infection. These findings provide a new mechanistic link with our current understanding of HIV/SIV pathogenesis and implicate MAIT cell depletion in the disease process.

scholarly journals Comparison of Simian Immunodeficiency Virus SIVagmVer Replication and CD4+ T-Cell Dynamics in Vervet and Sabaeus African Green Monkeys

2006 ◽  
Vol 80 (10) ◽  
pp. 4868-4877 ◽  
Author(s):  
Simoy Goldstein ◽  
Charles R. Brown ◽  
Ilnour Ourmanov ◽  
Ivona Pandrea ◽  
Alicia Buckler-White ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Models ◽  
Cell Dynamics ◽  
Ki 67 ◽  
Antiviral Immune Response ◽  
Wide Range ◽  
Immunodeficiency Virus ◽  
Experimental Inoculation ◽  
Siv Infection ◽  
Green Monkeys

ABSTRACT The simian immunodeficiency viruses (SIV) naturally infect a wide range of African primates, including African green monkeys (AGM). Despite moderate to high levels of plasma viremia in naturally infected AGM, infection is not associated with immunodeficiency. We recently reported that SIVagmVer90 isolated from a naturally infected vervet AGM induced AIDS following experimental inoculation of pigtailed macaques. The goal of the present study was to evaluate the replication of this isolate in two species of AGM, sabaeus monkeys (Chlorocebus sabaeus) and vervets (C. pygerythrus). Inoculation of sabaeus AGM with SIVagmVer90 resulted in low and variable primary and set-point viremia (<102 to 104 copies/ml). In contrast, inoculation of vervet AGM with either SIVagmVer90 or blood from a naturally infected vervet (Ver1) resulted in high primary viremia and moderate plateau levels, similar to the range seen in naturally infected vervets from this cohort. CD4+ T cells remained stable throughout infection, even in AGM with persistent high viremia. Despite the lack of measurable lymphadenopathy, infection was associated with an increased number of Ki-67+ T cells in lymph node biopsies, consistent with an early antiviral immune response. The preferential replication of SIVagmVer in vervet versus sabaeus AGM shows that it is critical to match AGM species and SIV strains for experimental models of natural SIV infection.

scholarly journals Human MAIT Cells Respond to Staphylococcus aureus with Enhanced Anti-Bacterial Activity

2022 ◽  
Vol 10 (1) ◽  
pp. 148
Author(s):  
Andrew J. R. Cooper ◽  
Jonah Clegg ◽  
Féaron C. Cassidy ◽  
Andrew E. Hogan ◽  
Rachel M. McLoughlin
Keyword(s):  
Staphylococcus Aureus ◽  
Cytokine Production ◽  
Cell Cytotoxicity ◽  
Mait Cells ◽  
Cell Responses ◽  
Potential Applications ◽  
Infected Cells ◽  
Great Relevance ◽  
Ongoing Development ◽  
Mait Cell

Mucosal-Associated Invariant T (MAIT) cells have been shown to play protective roles during infection with diverse pathogens through their propensity for rapid innate-like cytokine production and cytotoxicity. Among the potential applications for MAIT cells is to defend against Staphylococcus aureus, a pathogen of serious clinical significance. However, it is unknown how MAIT cell responses to S. aureus are elicited, nor has it been investigated whether MAIT cell cytotoxicity is mobilized against intracellular S. aureus. In this study, we investigate the capacity of human MAIT cells to respond directly to S. aureus. MAIT cells co-cultured with dendritic cells (DCs) infected with S. aureus rapidly upregulate CD69, express IFNγ and Granzyme B and degranulate. DC secretion of IL-12, but not IL-18, was implicated in this immune response, while TCR binding of MR1 is required to commence cytokine production. MAIT cell cytotoxicity resulted in apoptosis of S. aureus-infected cells, and reduced intracellular persistence of S. aureus. These findings implicate these unconventional T cells in important, rapid anti-S. aureus responses that may be of great relevance to the ongoing development of novel anti-S. aureus treatments.

scholarly journals Dynamics of Simian Immunodeficiency Virus Two-Long-Terminal-Repeat Circles in the Presence and Absence of CD8+Cells

2018 ◽  
Vol 92 (13) ◽  
pp. e02100-17 ◽  
Author(s):  
Benjamin B. Policicchio ◽  
Erwing Fabian Cardozo ◽  
Paola Sette ◽  
Cuiling Xu ◽  
George Haret-Richter ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Long Terminal Repeat ◽  
Simian Immunodeficiency Virus ◽  
Integrase Inhibitor ◽  
Terminal Repeat ◽  
Cell Depletion ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Infected Cells ◽  
Cd8 Depletion

ABSTRACTCD8+cells play a key role in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, but their specific mechanism(s) of action in controlling the virus is unclear. Two-long-terminal-repeat (2-LTR) circles are extrachromosomal products generated upon failed integration of HIV/SIV. To understand the specific effects of CD8+cells on infected cells, we analyzed the dynamics of 2-LTR circles in SIVmac251-infected rhesus macaques (RMs) treated with an integrase inhibitor (INT). Twenty RMs underwent CD8+cell depletion and received raltegravir (RAL) monotherapy or a combination of both. Blood, lymph nodes (LNs), and gut biopsy specimens were routinely sampled. Plasma viral loads (pVLs) and 2-LTR circles from peripheral blood mononuclear cells (PBMCs) and LN lymphocytes were measured with quantitative reverse transcription-PCR (qRT-PCR). In the CD8 depletion group, an ∼1-log increase in pVLs and a slow increase in PBMC 2-LTRs occurred following depletion. In the INT group, a strong decline in pVLs upon treatment initiation and no change in 2-LTR levels were observed. In the INT and CD8+cell depletion group, an increase in pVLs following CD8 depletion similar to that in the CD8 depletion group was observed, with a modest decline following INT initiation, and 2-LTR circles significantly increased in PBMCs and LNs. Analyzing the 2-LTR data across all treatment groups with a mathematical model indicates that the data best support an effect of CD8+cells in killing cells prior to viral integration. Sensitivity analyses of these results confirm that effect but also allow for additional effects, which the data do not discriminate well. Overall, we show that INT does not significantly increase the levels of 2-LTR circles. However, CD8+cell depletion increases the 2-LTR levels, which are enhanced in the presence of an INT.IMPORTANCECD8+T cells play an essential role in controlling HIV and SIV infection, but the specific mechanisms involved remain poorly understood. Due to failed viral infection, HIV and SIV can form 2-LTR extrachromosomal circles that can be quantified. We present novel data on the dynamics of these 2-LTR forms in a SIV-infected macaque model under three different treatment conditions: depletion of CD8+cells, administration of the integrase inhibitor in a monotherapy, which favors the formation of 2-LTR circles, and a combination of the two treatments. We used a new mathematical model to help interpret the data, and the results suggest that CD8+cells exert a killing effect on infected cells prior to virus integration. These results provide new insights into the mechanisms of action of CD8+cells in SIV infection. Confirmation of our results would be an important step in understanding immune control of HIV.

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