ORCID Profile
0000-0001-6081-8494
Current Organisations
Perron Institute for Neurological and Translational Science
,
Murdoch University
,
University of Notre Dame Australia
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Publisher: American Society of Hematology
Date: 11-2002
DOI: 10.1182/BLOOD-2002-01-0055
Abstract: We previously observed the presence of anti-human μ-opioid-receptor (anti-hMOR) autoantibodies in IgG pools prepared from several thousand healthy blood donors. These autoantibodies behaved agonistically because of their ability to bind to the first and third extracellular loops of the receptor. In this study, we found that each healthy donor's serum contained anti-hMOR IgG autoantibodies with a specific activity against both the first and the third extracellular loops of the receptor. Because of the inability of IgG to cross the blood-brain barrier, we investigated the effects of the expression of anti-hMOR autoantibodies on immune cells. In analogy to studies of the effects of morphine, we investigated the ability of antibodies to sensitize splenocytes to Fas (CD95)-mediated apoptosis. We took advantage of the high sequence homology between murine MOR and hMOR extracellular loops to estimate the effect on murine splenocytes of anti-hMOR antibodies raised by immunizing mice. Splenocytes from mice injected with Chinese hamster ovary (CHO) cells expressing MOR were sensitized to Fas-mediated apoptosis, whereas those from mice injected with CHO cells or phosphate-buffered saline were not. Similar sensitization to Fas-mediated apoptosis was observed in splenocytes from mice undergoing passive transfer either with IgG from mice previously immunized against CHO cells expressing MOR or with IgG directed against the first and third extracellular loops of the receptor. Together, our data show that anti-MOR autoantibodies are commonly expressed in healthy humans and could participate in the control of lymphocyte homeostasis by promoting Fas-mediated apoptosis.
Publisher: The American Association of Immunologists
Date: 02-2011
Abstract: The Ly49H activating receptor on C57BL/6 (B6) NK cells plays a key role in early resistance to murine cytomegalovirus (MCMV) infection through specific recognition of the MCMV-encoded MHC class I-like molecule m157 expressed on infected cells. The m157 molecule is also recognized by the Ly49I inhibitory receptor from the 129/J mouse strain. The m157 gene is highly sequence variable among MCMV isolates, with many m157 variants unable to bind Ly49HB6. In this study, we have sought to define if m157 variability leads to a wider spectrum of interactions with other Ly49 molecules and if this modifies host susceptibility to MCMV. We have identified novel m157–Ly49 receptor interactions, involving Ly49C inhibitory receptors from B6, BALB/c, and NZB mice, as well as the Ly49HNZB activation receptor. Using an MCMV recombinant virus in which m157K181 was replaced with m157G1F, which interacts with both Ly49HB6 and Ly49CB6, we show that the m157G1F–Ly49C interactions cause no apparent attenuating effect on viral clearance in B6 mice. Hence, when m157 can bind both inhibitory and activation NK cell receptors, the outcome is still activation. Thus, these data indicate that whereas m157 variants predominately interact with inhibitory Ly49 receptors, these interactions do not profoundly interfere with early NK cell responses.
Publisher: Wiley
Date: 11-2008
Abstract: Effective immunity requires coordinated activation of innate and adaptive immune responses. NK cells are principal mediators of innate immunity, able to respond to challenge quickly and generally without prior activation. The most acknowledged functions of NK cells are their cytotoxic potential and their ability to release large amounts of cytokines, especially IFN-gamma. Recently, it has become clear that NK cells are more than assassins. Indeed, NK cells play critical roles in shaping adaptive immunity.
Publisher: American Society of Hematology
Date: 09-2005
DOI: 10.1182/BLOOD-2005-01-0337
Abstract: Intrathymic T-cell maturation critically depends on the selective expansion of thymocytes expressing a functionally rearranged T-cell receptor (TCR) β chain. In addition, TCR-independent signals also contribute to normal T-cell development. It is unclear whether and how signals from the 2 types of pathways are integrated. Here, we show that T-cell factor-1 (TCF-1), a nuclear effector of the canonical wingless/int (wnt)/catenin signaling pathway, ensures the survival of proliferating, pre-TCR+ thymocytes. The survival of pre-TCR+ thymocytes requires the presence of the N-terminal catenin-binding domain in TCF-1. This domain can bind the transcriptional coactivator β-catenin and may also bind γ-catenin (plakoglobin). However, in the absence of γ-catenin, T-cell development is normal, supporting a role for β-catenin. Signaling competent β-catenin is present prior to and thus arises independently from pre-TCR signaling and does not substantially increase on pre-TCR signaling. In contrast, pre-TCR signaling significantly induces TCF-1 expression. This coincides with the activation of a wnt/catenin/TCF reporter transgene in vivo. Collectively, these data suggest that efficient TCF-dependent transcription requires that pre-TCR signaling induces TCF-1 expression, whereas wnt signals may provide the coactivator such as β-catenin. The 2 pathways thus have to cooperate to ensure thymocyte survival at the pre-TCR stage. (Blood. 2005 :1726-1733)
Publisher: American Society of Hematology
Date: 08-2008
DOI: 10.1182/BLOOD-2007-10-120089
Abstract: Natural killer (NK)–cell alloreactivity is exploited in bone marrow transplantation to improve clinical outcome. Likewise, in solid organ transplantation, it has been recently shown that recipient NK cells may limit alloreactive T-cell responses through their capacity to prevent the persistence of graft-derived allogeneic dendritic cells (DCs). In a model of CD4+ T cell–mediated allogeneic skin graft rejection, we show that the absence of host NK-cell alloreactivity was characterized by enhanced expansion of alloreactive effector T lymphocytes, including Th2 cells, and massive eosinophilic infiltrates in the rejected tissues. In CD8+ T cell–deficient C57BL/6 (H-2b) recipients injected with allogeneic BALB/c (H-2d) DCs, we demonstrated that NK cells expressing the H-2Dd-specific Ly49D activating receptor were implicated in the regulation of alloreactive CD4+ T-cell responses. Moreover, we showed that Ly49D+ CD127− NK cells were recruited within DC draining lymph nodes and rapidly eliminated allogeneic H-2d DCs through the perforin pathway. In normal mice, we further demonstrated that NK cells by quickly eliminating allogeneic DCs strongly inhibited alloreactive CD8+ T-cell responses. Thus, NK cells act as early regulators of alloreactive T-cell priming in allotransplantation through their capacity to kill allogeneic DCs in draining lymph nodes.
Publisher: American Society for Clinical Investigation
Date: 15-04-2000
DOI: 10.1172/JCI9243
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.BERH.2022.101761
Abstract: Inclusion body myositis (IBM) is a slowly progressive muscle disease affecting ageing in iduals. IBM presents with a distinctive pattern of weakness involving the quadriceps and finger flexor muscles, although other muscles including pharyngeal muscles become affected over time. Pathological hallmarks of IBM include autoimmune features, including endomysial infiltration by highly differentiated T cells, as well as degenerative features marked by intramyofibre protein aggregates organised into inclusion bodies. Despite some progress in understanding the cellular pathways involved in IBM, it remains untreatable, and the progression of the disease leads to progressive weakness, disability, wheelchair dependency and loss of independence. Therefore, there is an urgent need to improve our understanding of the underlying mechanisms and pathways involved in this disease to identify new treatment targets. Here, we discuss the current understanding of aetiopathogenesis, the interrelationship between autoimmunity and degeneration, and how ageing is a major influencer of both these features.
Publisher: The American Association of Immunologists
Date: 07-2016
Abstract: NK cells possess inhibitory receptors that are responsible for self-MHC class I recognition beyond their inhibitory function, accumulating evidence indicates that such receptors confer NK cell functional competence through an unclear process termed “licensing.” Ly49C is the main self-specific inhibitory Ly49 receptor in H-2b C57BL/6 (B6) mice. We used B6 Ly49C-transgenic and B6 β2 microglobulin (β2m)-knockout Ly49C-transgenic mice to investigate the impact of licensing through this inhibitory receptor in precursor and mature NK cells. We found that self-specific inhibitory receptors affected NK cell precursor survival and proliferation at particular developmental stages in an MHC class I–dependent manner. The presence of Ly49C impacted the NK cell repertoire in a β2m-dependent manner, with reduced Ly49A+, Ly49G2+, and Ly49D+ subsets, an increased DNAM-1+ subset, and higher NKG2D expression. Licensed NK cells displayed a skewed distribution of the maturation stages, which was characterized by differential CD27 and CD11b expression, toward the mature phenotypes. We found that Ly49C-mediated licensing induced a split effect on NK cell functions, with increased cytokine-production capabilities following engagement of various activating receptors while cytotoxicity remained unchanged. Analysis of licensed NK cell functions in vivo, in a system of mouse CMV infection, indicated that licensing did not play a major role in the NK cell antiviral response during acute infection, but it strongly impaired the generation and/or persistence of memory NK cells. This study unravels multifaceted effects of licensing on NK cell populations and their functions.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2013
DOI: 10.1038/NI.2605
Abstract: Activating and inhibitory receptors on natural killer (NK) cells have a crucial role in innate immunity, although the basis of the engagement of activating NK cell receptors is unclear. The activating receptor Ly49H confers resistance to infection with murine cytomegalovirus by binding to the 'immunoevasin' m157. We found that m157 bound to the helical stalk of Ly49H, whereby two m157 monomers engaged the Ly49H dimer. The helical stalks of Ly49H lay centrally across the m157 platform, whereas its lectin domain was not required for recognition. Instead, m157 targeted an 'aromatic peg motif' present in stalks of both activating and inhibitory receptors of the Ly49 family, and substitution of this motif abrogated binding. Furthermore, ligation of m157 to Ly49H or Ly49C resulted in intracellular signaling. Accordingly, m157 has evolved to 'tackle the legs' of a family of NK cell receptors.
Publisher: Springer Science and Business Media LLC
Date: 11-03-2021
DOI: 10.1038/S41586-021-03412-7
Abstract: Transmission of SARS-CoV-2 is uncontrolled in many parts of the world control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant
Publisher: American Chemical Society (ACS)
Date: 16-03-2021
Publisher: Frontiers Media SA
Date: 12-08-2021
DOI: 10.3389/FIMMU.2021.712722
Abstract: The activating immune receptor natural killer group member D (NKG2D) and its cognate ligands represent a fundamental surveillance system of cellular distress, damage or transformation. Signaling through the NKG2D receptor-ligand axis is critical for early detection of viral infection or oncogenic transformation and the presence of functional NKG2D ligands (NKG2D-L) is associated with tumor rejection and viral clearance. Many viruses and tumors have developed mechanisms to evade NKG2D recognition via transcriptional, post-transcriptional or post-translational interference with NKG2D-L, supporting the concept that circumventing immune evasion of the NKG2D receptor-ligand axis may be an attractive therapeutic avenue for antiviral therapy or cancer immunotherapy. To date, the complexity of the NKG2D receptor-ligand axis and the lack of specificity of current NKG2D-targeting therapies has not allowed for the precise manipulation required to optimally harness NKG2D-mediated immunity. However, with the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins, novel opportunities have arisen in the realm of locus-specific gene editing and regulation. Here, we give a brief overview of the NKG2D receptor-ligand axis in humans and discuss the levels at which NKG2D-L are regulated and dysregulated during viral infection and oncogenesis. Moreover, we explore the potential for CRISPR-based technologies to provide novel therapeutic avenues to improve and maximize NKG2D-mediated immunity.
Publisher: Frontiers Media SA
Date: 30-03-2023
DOI: 10.3389/FIMMU.2023.1153789
Abstract: Inclusion body myositis (IBM) is a progressive inflammatory myopathy characterised by skeletal muscle infiltration and myofibre invasion by CD8 + T lymphocytes. In some cases, IBM has been reported to be associated with a systemic lymphoproliferative disorder of CD8 + T cells exhibiting a highly differentiated effector phenotype known as T cell Large Granular Lymphocytic Leukemia (T-LGLL). We investigated the incidence of a CD8 + T-LGL lymphoproliferative disorder in 85 IBM patients and an aged-matched group of 56 Healthy Controls (HC). Further, we analysed the phenotypical characteristics of the expanded T-LGLs and investigated whether their occurrence was associated with any particular HLA alleles or clinical characteristics. Blood cell analysis by flow cytometry revealed expansion of T-LGLs in 34 of the 85 (40%) IBM patients. The T cell immunophenotype of T-LGL HIGH patients was characterised by increased expression of surface molecules including CD57 and KLRG1, and to a lesser extent of CD94 and CD56 predominantly in CD8 + T cells, although we also observed modest changes in CD4 + T cells and γδ T cells. Analysis of Ki67 in CD57 + KLRG1 + T cells revealed that only a small proportion of these cells was proliferating. Comparative analysis of CD8 + and CD4 + T cells isolated from matched blood and muscle s les donated by three patients indicated a consistent pattern of more pronounced alterations in muscles, although not significant due to small s le size. In the T-LGL HIGH patient group, we found increased frequencies of perforin-producing CD8 + and CD4 + T cells that were moderately correlated to combined CD57 and KLRG1 expression. Investigation of the HLA haplotypes of 75 IBM patients identified that carriage of the HLA-C*14:02:01 allele was significantly higher in T-LGL HIGH compared to T-LGL LOW in iduals. Expansion of T-LGL was not significantly associated with seropositivity patient status for anti-cytosolic 5'-nucleotidase 1A autoantibodies. Clinically, the age at disease onset and disease duration were similar in the T-LGL HIGH and T-LGL LOW patient groups. However, metadata analysis of functional alterations indicated that patients with expanded T-LGL more frequently relied on mobility aids than T-LGL LOW patients indicating greater disease severity. Altogether, these results suggest that T-LGL expansion occurring in IBM patients is correlated with exacerbated immune dysregulation and increased disease burden.
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1416
Abstract: Sporadic Inclusion Body Myositis (IBM) is an inflammatory muscle disease affecting in iduals over the age of 45, leading to progressive muscle wasting, disability and loss of independence. Histologically, IBM is characterised by immune changes including myofibres expressing major histocompatibility complex molecules and invaded by CD8 + T cells and macrophages, and by degenerative changes including protein aggregates organised in inclusion bodies, rimmed vacuoles and mitochondrial abnormalities. There is currently no cure, and regular exercise is currently the only recognised treatment effective at limiting muscle weakening, atrophy and loss of function. Testosterone exerts anti‐inflammatory effects, inhibiting effector T‐cell differentiation and pro‐inflammatory cytokine production. We conducted a double‐blind, placebo‐controlled, cross‐over trial in men with IBM, to assess whether a personalised progressive exercise training combined with application of testosterone, reduced the inflammatory immune response associated with this disease over and above exercise alone. To assess intervention efficacy, we immunophenotyped blood immune cells by flow cytometry, and measured serum cytokines and chemokines by Luminex immunoassay. Testosterone supplementation resulted in modest yet significant count reduction in the classical monocyte subset as well as eosinophils. Testosterone‐independent immunoregulatory effects attributed to exercise included altered proportions of some monocyte, T‐ and B‐cell subsets, and reduced IL‐12, IL‐17, TNF‐α, MIP‐1β and sICAM‐1 in spite of interin idual variability. Overall, our findings indicate anti‐inflammatory effects of exercise training in IBM patients, whilst concomitant testosterone supplementation provides some additional changes. Further studies combining testosterone and exercise would be worthwhile in larger cohorts and longer testosterone administration periods.
Publisher: Elsevier
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 20-01-2005
Publisher: International Union Against Tuberculosis and Lung Disease
Date: 21-03-2022
DOI: 10.5588/PHA.21.0071
Abstract: BACKGROUND: The level of antibiotic resistance of pathogens causing uncomplicated urinary tract infections (UTIs) is increasing. The 2017–2018 GLASS (Global Antimicrobial Resistance and Use Surveillance System) report indicated % resistance to ceftriaxone and ciprofloxacin in Escherichia coli in Pakistan. METHODS: A prospective study was conducted in the Médecins Sans Frontières (MSF) supported Timurgara District Hospital, Timurgara, Pakistan, from September 2017 to December 2018. Women aged 18–65 years presenting to the Emergency Department with symptoms of uncomplicated UTI (cystitis yelonephritis) were invited to participate. We conducted microbiological culture and sensitivity testing for s les with positive dipstick or nitrite test. RESULTS: Of the 200 patients who participated, 109 (54.5%) were diagnosed with pyelonephritis and 91 (45.5%) with cystitis. Forty-three s les (21.5%) were culture-positive: E. coli was isolated in 27 s les, Enterococcus spp. in 7 and Klebsiella pneumoniae in 6. Overall resistance to ciprofloxacin was observed in 51.8% of E. coli isolates, and ceftriaxone resistance in 66.7% of E. coli isolates and in 33.3% of K. pneumoniae . Resistance to fosfomycin was low (one E. coli isolate). CONCLUSIONS: This study found resistance to first- and second-line antibiotics for treating UTIs as per the MSF protocol. Heightened awareness and potential changes to local prescription practices are necessary to curb the spread of antimicrobial resistance pathogens causing UTIs.
Publisher: The American Association of Immunologists
Date: 02-2007
DOI: 10.4049/JIMMUNOL.178.3.1277
Abstract: The Ly49A NK cell receptor interacts with MHC class I (MHC-I) molecules on target cells and negatively regulates NK cell-mediated target cell lysis. We have recently shown that the MHC-I ligand-binding capacity of the Ly49A NK cell receptor is controlled by the NK cells’ own MHC-I. To see whether this property was unique to Ly49A, we have investigated the binding of soluble MHC-I multimers to the Ly49 family receptors expressed in MHC-I-deficient and -sufficient C57BL/6 mice. In this study, we confirm the binding of classical MHC-I to the inhibitory Ly49A, C and I receptors, and demonstrate that detectable MHC-I binding to MHC-I-deficient NK cells is exclusively mediated by these three receptors. We did not detect significant multimer binding to stably transfected or NK cell-expressed Ly49D, E, F, G, and H receptors. Yet, we identified the more distantly related Ly49B and Ly49Q, which are not expressed by NK cells, as two novel MHC-I receptors in mice. Furthermore, we show using MHC-I-sufficient mice that the NK cells’ own MHC-I significantly masks the Ly49A and Ly49C, but not the Ly49I receptor. Nevertheless, Ly49I was partly masked on transfected tumor cells, suggesting that the structure of Ly49I is compatible in principal with cis binding of MHC-I. Finally, masking of Ly49Q by cis MHC-I was minor, whereas masking of Ly49B was not detected. These data significantly extend the MHC-I specificity of Ly49 family receptors and show that the accessibility of most, but not all, MHC-I-binding Ly49 receptors is modulated by the expression of MHC-I in cis.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2021
DOI: 10.1038/S41586-021-03739-1
Abstract: Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in in iduals above eighty years of age 1 . Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine 2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older in iduals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Public Library of Science (PLoS)
Date: 29-05-2014
Publisher: Springer Science and Business Media LLC
Date: 05-02-2021
Publisher: American Chemical Society (ACS)
Date: 11-01-2021
Publisher: Public Library of Science (PLoS)
Date: 11-04-2023
DOI: 10.1371/JOURNAL.PONE.0283394
Abstract: Inclusion body myositis (IBM) is the most commonly acquired skeletal muscle disease of older adults involving both autoimmune attack and muscle degeneration. As exercise training can improve outcomes in IBM, this study assessed whether a combination of testosterone supplementation and exercise training would improve muscle strength, physical function and quality of life in men affected by IBM, more than exercise alone. This pilot study was a single site randomised, double-blind, placebo-controlled, crossover study. Testosterone (exercise and testosterone cream) and placebo (exercise and placebo cream) were each delivered for 12 weeks, with a two-week wash-out between the two periods. The primary outcome measure was improvement in quadriceps isokinetic muscle strength. Secondary outcomes included assessment of isokinetic peak flexion force, walk capacity and patient reported outcomes, and other tests, comparing results between the placebo and testosterone arms. A 12-month Open Label Extension (OLE) was offered using the same outcome measures collected at 6 and 12-months. 14 men completed the trial. There were no significant improvements in quadriceps extension strength or lean body mass, nor any of the secondary outcomes. Improvement in the RAND Short Form 36 patient reported outcome questionnaire ‘emotional wellbeing’ sub-category was reported during the testosterone arm compared to the placebo arm (mean difference [95% CI]: 6.0 points, [95% CI 1.7,10.3]). The OLE demonstrated relative disease stability over the 12-month period but with a higher number of testosterone-related adverse events. Adding testosterone supplementation to exercise training did not significantly improve muscle strength or physical function over a 12-week intervention period, compared to exercise alone. However, the combination improved emotional well-being over this period, and relative stabilisation of disease was found during the 12-month OLE. A longer duration trial involving a larger group of participants is warranted.
Publisher: Future Medicine Ltd
Date: 02-2015
DOI: 10.2217/FVL.14.106
Abstract: ABSTRACT NK cells constitute a population of lymphocytes involved in innate immune functions. They play a critical role in antiviral immune surveillance. Viruses have evolved with their host species for millions of years, each exerting a selective pressure upon the other. As a corollary, the pathways used by the immune system that are critical to control viral infection can be revealed by defining the role of viral gene products that are nonessential for virus replication. We relate here the battery of resources available to NK cells to recognize and eliminate viruses and reciprocally the immune evasion mechanisms developed by viruses to prevent NK cell activation.
Publisher: American Society of Hematology
Date: 10-2006
DOI: 10.1182/BLOOD-2005-10-4059
Abstract: Accumulating evidence indicates that, in absence of CD8+ T-cell activation, CD4+ T-cell–mediated allograft rejection is associated with a dominant Th2-cell response and eosinophil infiltrates. In this study, we analyzed the mechanisms by which CD8+ T cells regulate alloreactive CD4+ T-cell priming and differentiation into interleukin 4 (IL-4)–producing cells. We showed that interferon γ (IFN-γ) production by CD8+ T cells was dispensable for the inhibition of Th2-cell development, as well as tissue eosinophilia and type 2 cytokine production in the rejected grafts. Since we noticed that CD8+ T cells not only suppressed Th2 differentiation, but also down-modulated the overall priming of alloreactive CD4+ T cells, we evaluated whether CD8+ T cells act by limiting the accumulation of donor-derived dendritic cells (DCs) in lymph nodes. We found that indeed, alloreactive CD8+ T cells rapidly eliminated allogeneic DCs from T-cell areas of draining lymph nodes, through a perforin-dependent mechanism. Thus, our data demonstrate that cytotoxic T lymphocyte (CTL)–mediated clearance of allogeneic DCs is a negative feedback mechanism that limits the duration of alloantigen presentation in draining lymph nodes, thereby modulating the litude and polarization of the primary alloreactive CD4+ T-cell responses.
Publisher: Wiley
Date: 02-2003
Abstract: It is widely accepted that females have superior immune responses than males, but the ways by which sex hormones may enhance T cell responses are still poorly understood. In the present study, we analyzed the effect of estrogens on CD4 T cell activation and differentiation after immunization with exogenous antigens. We show that administration of low doses of 17beta-estradiol (E2) to castrated female mice results in a striking increase of antigen-specific CD4 T cell responses and in the selective development of IFN-gamma-producing cells. Quantitative assessment of the frequency of T cells bearing a public TCR beta chain CDR3 motif demonstrated that the clonal size of primary antigen-specific CD4 T cells was dramatically increased in immune lymph nodes from E2-treated mice. By using mice with disrupted estrogen receptor (ER) alpha or beta genes, we show that ERalpha, but not ERbeta, was necessary for the enhanced E2-driven Th1 cell responsiveness. Furthermore, ERalpha expression in hematopoietic cells was essential, since E2 effects on Th1 responses were only observed in mice reconstituted with bone marrow cells from ERalpha+/+, but not ERalpha-deficient mice. These results demonstrate that estrogen administration promotes strong antigen-specific Th1 cell responses in a mechanism that requires functional expression of ERalpha in hematopoietic cells.
Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1016/S0952-7915(02)00031-6
Abstract: The identification of NK cell receptors specific for MHC class I molecules has greatly improved our knowledge of NK cell reactivity and specificity. Inhibitory receptors prevent NK cell activation directed against cells expressing self-MHC class I molecules. Consequently, diseased cells that do not express self-MHC class I molecules become susceptible to NK cell-mediated attack. Because of the specificity and distribution of inhibitory NK cell receptors, cells that express non-self (allogeneic) MHC class I molecules are also susceptible to NK cell reactions. This feature has been exploited in a clinical setting to treat leukemia patients.
Publisher: The American Association of Immunologists
Date: 11-2000
DOI: 10.4049/JIMMUNOL.165.9.4994
Abstract: The mechanisms that influence the polarization of CD4 T cells specific for allogeneic MHC class II molecules in vivo are still poorly understood. We have examined the pathway of alloreactive CD4 T cell differentiation in a situation in which only CD4 T cells could be activated in vivo. In this report we show that priming of adult mice with allogeneic APC, in the absence of MHC class I-T cell interactions, induces a strong expansion of type 2 cytokine-producing allohelper T cells. These alloantigen-specific CD4 T cells directly recognize native allogeneic MHC class II molecules on APC and secrete, in addition to the prototypic Th2 cytokines IL-4, IL-5, and IL-10, large amounts of TGF-β. The default Th2-phenotype acquisition is not genetically controlled and occurred both in BALB/c and C57BL/6 mice. CD8 T cells are the principal cell type that controls CD4 T cell differentiation in vivo. Furthermore, we demonstrate that strong Th2 priming can be induced not only with allogeneic splenocytes but also with a low number of bone marrow-derived dendritic cells. Finally, using a passive transfer system, we provide direct evidence that CD8 T cell expansion in situ promotes alloreactive Th1 cell development principally by preventing their default development to the Th2 pathway in a mechanism that is largely IFN-γ independent. Therefore, this work demonstrates that type 2 cytokine production represents a dominant pathway of alloreactive CD4 T cell differentiation in adult mice, a phenomenon that was initially thought to occur only during the neonatal period.
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.SEMCANCER.2006.07.008
Abstract: Natural killer (NK) cells have originally been identified based on their capacity to kill transformed cells in a seemingly non-specific fashion. Over the last 15 years, knowledge on receptor ligand systems used by NK cells to specifically detect transformed cells has been accumulating rapidly. One of these receptor ligand systems, the NKG2D pathway, has received particular attention, and now serves as a paradigm for how the immune system is able to gather information about the health status of autologous host cells. In addition to its significance on NK cells, NKG2D, as well as other NK cell receptors, play significant roles on T cells. This review aims at summarizing recent insights into the regulation of NKG2D function, the control over NKG2D ligand expression and the role of NKG2D in tumor immunity. Finally, we will discuss first attempts to exploit NKG2D function to improve immunity to tumors.
Publisher: Wiley
Date: 10-2006
Abstract: There is growing evidence that lymphocytes impact the development and/or function of other lymphocyte populations. Based on such observations we have tested whether the NK cell compartment was phenotypically and functionally altered in the absence of B and/or T cells. Here we show that T cell deficiency significantly accelerates BM NK cell production and the subsequent seeding of splenic and liver NK cell compartments. In contrast, B cell deficiency reduces splenic NK cell survival. In the absence of T and B cells, the size of the NK cell compartments is determined by the combination of these positive and negative effects. Even though NK cell homeostasis is significantly altered, NK cells from T and/or B cell-deficient mice show a normal capacity to kill a susceptible target cell line and to produce IFN. Nevertheless, we noted that the usage of MHC class I-specific Ly49 family receptors was significantly altered in the absence of T and/or B cells. In general, B cell deficiency expanded Ly49 receptor usage, while T cell deficiency exerted both positive and negative effects. These findings show that B and T cells significantly and differentially influence the homeostasis and the phenotype of NK cells.
Publisher: The American Association of Immunologists
Date: 15-09-2002
DOI: 10.4049/JIMMUNOL.169.6.2979
Abstract: Although much progress has been made in understanding the role of NK cells in bone marrow transplantation, little is known about their function in CD4 T cell-mediated allograft rejection. We have previously shown that in the absence of CD8 T lymphocyte priming, the in vivo default development pathway of alloreactive CD4 T cells was strongly biased toward Th2 phenotype acquisition. In this study, we investigate the impact of NK cells on the activation and differentiation of alloreactive CD4 T cells in various donor/recipient combinations. Our data demonstrate that defective inhibition of host NK cells by donor APCs including dendritic cells (DCs) results in diminished allospecific Th cell responses associated with the development of effector Th cells producing IFN-γ rather than type 2 cytokines. Turning host NK cells off was sufficient to restore strong alloreactive CD4 T cell priming and Th2 cell development. Similar results were obtained by analyzing the effect of NK cell activation on CD4 T cell responses to skin allografts. However, despite the dramatic effect of NK cells on alloreactive Th1/Th2 cell development, the kinetics of skin graft rejection were not affected. Thus, Th2 differentiation is a major pathway of alloreactive CD4 T cell development during solid organ transplant rejection, as long as host NK and CD8 T cells are not activated. We propose the hypothesis that MHC class I-driven interactions between donor DCs and host NK cells or CD8 T cells might result in DC-carried signals controlling the dynamics of alloreactive CD4 T cell priming and polarization.
Publisher: American Society of Hematology
Date: 04-2008
DOI: 10.1182/BLOOD-2007-07-100057
Abstract: NKG2D is a multisubunit activation receptor that allows natural killer (NK) cells to detect and eliminate stressed, infected, and transformed host cells. However, the chronic exposure of NK cells to cell-bound NKG2D ligands has been shown to impair NKG2D function both in vitro and in vivo. Here we have tested whether continuous NKG2D engagement selectively impacted NKG2D function or whether heterologous NK cell activation pathways were also affected. We found that sustained NKG2D engagement induced cross-tolerization of several unrelated NK cell activation receptors. We show that receptors that activate NK cells via the DAP12/KARAP and DAP10 signaling adaptors, such as murine NKG2D and Ly49D, cross-tolerize preferentially NK cell activation pathways that function independent of DAP10/12, such as antibody-dependent cell-mediated cytotoxicity and missing-self recognition. Conversely, DAP10/12-independent pathways are unable to cross-tolerize unrelated NK cell activation receptors such as NKG2D or Ly49D. These data define a class of NK cell activation receptors that can tolerize mature NK cells. The reversible suppression of the NK cells' cytolytic function probably reduces the NK cells' efficacy to control endogenous and exogenous stress yet may be needed to limit tissue damage.
Publisher: American Society of Hematology
Date: 09-2005
DOI: 10.1182/BLOOD-2005-03-0918
Abstract: NKG2D is an activation receptor that allows natural killer (NK) cells to detect diseased host cells. The engagement of NKG2D with corresponding ligand results in surface modulation of the receptor and reduced function upon subsequent receptor engagement. However, it is not clear whether in addition to modulation the NKG2D receptor complex and/or its signaling capacity is preserved. We show here that the prolonged encounter with tumor cell-bound, but not soluble, ligand can completely uncouple the NKG2D receptor from the intracellular mobilization of calcium and the exertion of cell-mediated cytolysis. However, cytolytic effector function is intact since NKG2D ligand-exposed NK cells can be activated via the Ly49D receptor. While NKG2D-dependent cytotoxicity is impaired, prolonged ligand exposure results in constitutive interferon γ (IFNγ) production, suggesting sustained signaling. The functional changes are associated with a reduced presence of the relevant signal transducing adaptors DNAX-activating protein of 10 kDa (DAP-10) and killer cell activating receptor-associated protein/DNAX-activating protein of 12 kDa (KARAP/DAP-12). That is likely the consequence of constitutive NKG2D engagement and signaling, since NKG2D function and adaptor expression is restored to normal when the stimulating tumor cells are removed. Thus, the chronic exposure to tumor cells expressing NKG2D ligand alters NKG2D signaling and may facilitate the evasion of tumor cells from NK cell reactions. (Blood. 2005 :1711-1717)
Publisher: Frontiers Media SA
Date: 14-06-2016
Publisher: MDPI AG
Date: 16-10-2021
DOI: 10.3390/MPS4040075
Abstract: In inflammatory myopathies, the self-reactive immune cells involved in muscle aggression have been studied mostly using histological assessment of muscle biopsy sections this methodology provides the advantage of visualizing and identifying cells within the tissue, but it does not allow further investigation. To gain access to live and isolated cells, many studies utilized blood s les however, in the absence of biological tools to discriminate the leukocytes associated with the autoimmune process from those that emerged from responses against pathogens, the information observed on circulating immune cells often lacks in specificity, and thus result interpretation may prove difficult. In order to selectively retrieve self-reactive immune cells, we developed a protocol to isolate live leukocytes from human muscle biopsies, which allows for further analysis using a large range of methodologies. The protocol uses enzymatic digestion to release live leukocytes from freshly collected skeletal muscle s les, followed by filtration and separation of the leukocytes from the myocytes by density gradient centrifugation. The isolated cells can be submitted immediately to various analysis strategies to characterize ex vivo the specific cellular and molecular mechanisms responsible for self-directed immune muscle aggression or may be placed in culture for expansion.
Publisher: American Association for Cancer Research (AACR)
Date: 31-05-2012
DOI: 10.1158/0008-5472.CAN-11-3379
Abstract: During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1–dependent tumor progression in NK cell–controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit− (CD11b−) into Kit+ natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit+ NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit+ NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1–dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18–binding protein dramatically reduced the accumulation of Kit+CD11b− NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit+CD11b− NK cells endowed with B7-H1–dependent immunoablative functions in mice. Cancer Res 72(11) 2757–67. ©2012 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 14-02-2017
DOI: 10.1158/0008-5472.CAN-17-2826
Abstract: Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs antitumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK-cell–specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays. Moreover, targeting A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Taken together, our results establish A2AR-mediated adenosine signaling as an intrinsic negative regulator of NK-cell maturation and antitumor immune responses. On the basis of these findings, we propose that administering A2AR antagonists concurrently with NK cell–based therapies may heighten therapeutic benefits by augmenting NK cell–mediated antitumor immunity. Significance: Ablating adenosine signaling is found to promote natural killer cell maturation and antitumor immunity and reduce tumor growth. Cancer Res 78(4) 1003–16. ©2017 AACR.
Publisher: Public Library of Science (PLoS)
Date: 11-12-2014
Location: Australia
No related grants have been discovered for Jerome David Coudert.