38 results found
Wong K, Harker J, Dolgoter A, et al., T cell-intrinsic IL6R signaling is required for optimal ICOS expression and viral control during chronic infection, Journal of Immunology, ISSN: 1550-6606
The pleiotropic cytokine interleukin-6 (IL-6) plays an integral role not only in innate inflammatory responses but also in the activation and differentiation of lymphocyte subsets. Here, by using a conditional knockout model with selective IL-6 receptor deletion in T cells (IL6R-cKO), we demonstrated that T cell-specific IL6R signaling is essential for viral control during persistent lymphocytic choriomeningitis virus (LCMV) Clone 13 infection. Strikingly, we observed that in contrast to previous studies with ubiquitous IL-6 deletion or blockade, specific IL6R deletion in T cells did not affect T follicular helper (Tfh) accumulation unless IL6R-deficient T cells were competing with wildtype cells in mixed bone marrow chimeras. On the other hand, Tfh cells from IL6R-cKO infected mice exhibited reduced ICOS expression in both chimeric and non-chimeric settings, and this sole identifiable Tfh defect was associated with reduced germinal centres, compromised immunoglobulin switch and low avidity of LCMV-specific antibodies despite intact IL6R expression in B cells. We posit that IL6R cis-signaling is absolutely required for appropriate ICOS expression in Tfh cells and provides a competitive advantage for Tfh accumulation, enabling generation of optimal B cell and antibody responses, and ultimately viral control during in vivo chronic infection.
Uwadiae F, Pyle C, Walker S, et al., 2019, Targeting the ICOS/ICOS-L pathway in a mouse model of established allergic asthma disrupts T follicular helper cell responses and ameliorates disease, Allergy, Vol: 74, Pages: 650-662, ISSN: 0105-4538
BackgroundAllergic asthma is characterized by chronic inflammation and remodelling of the airways, associated with dysregulated type 2 immune responses and allergen‐specific IgE. T follicular helper cells (TFH) are crucial in T‐dependent B cell responses and have been implicated in allergic airway disease (AAD). TFH, unlike other CD4+ T cells are uniquely reliant on continuous ICOS signalling to maintain their phenotype after T cell priming, therefore disrupting this signal can impair TFH responses. However, the contribution of TFH to disease during chronic aero‐allergen exposure and the therapeutic potential of targeting these cells has not been evaluated.MethodsTo establish AAD, female BALB/c mice were repeatedly exposed to house dust mite or Alternaria alternata three times a week for up to 5 weeks. To examine the impact of TFH on AAD, mice were allergen exposed for 5 weeks and co‐administered anti‐ICOS‐Ligand targeted antibodies, 3 times for the last 2 weeks.ResultsTFH were first observed in the lung draining lymph nodes and with further exposure were also found locally within the lungs. TFH accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted TFH but did not affect the differentiation of other CD4+ T cell subsets. This reduced GC responses, allergen‐specific IgE, inflammation, pulmonary IL‐13 and airway hyper‐responsiveness.ConclusionsTFH are crucial in the regulation of AAD and the ICOS/ICOS‐L pathway could represent a novel therapeutic target in allergic asthma.
Lloyd CM, Harker JA, 2018, Epigenetic control of interleukin-9 in asthma, New England Journal of Medicine, Vol: 379, Pages: 87-89, ISSN: 0028-4793
Harker J, Wong K, Dallari S, et al., 2018, IL-27R signalling mediates early viral containment and impacts innate and adaptive immunity after chronic lymphocytic choriomeningitis virus infection, Journal of Virology, Vol: 92, ISSN: 1098-5514
Chronic viral infections represent a major challenge to host's immune response and a unique network of immunological elements, including cytokines, are required for their containment. By using a model persistent infection with the natural murine pathogen lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) we investigated the role of one such cytokine, interleukin 27 (IL-27), in the control of chronic infection. We found that IL-27R signalling promoted control of LCMV Cl13 as early as day 1 and 5 after infection and that il27p28 transcripts were rapidly elevated in multiple subsets of dendritic cells (DCs) and myeloid cells. In particular, plasmacytoid DCs (pDCs), the most potent type-1-interferon (IFN-I) producing cells, significantly increased il27p28 in a TLR7 dependent fashion. Notably, mice deficient in IL-27 specific receptor (R), WSX-1, exhibited a pleiotropy of innate and adaptive immune alterations after chronic LCMV infection, including compromised NK cell cytotoxicity and antibody responses. While, the majority of these immune alterations appeared cell-extrinsic, cell-intrinsic IL-27R was necessary to maintain early pDC numbers, which, alongside lower IFN-I transcription in CD11b+ DCs and myeloid cells, may explain the compromised IFN-I elevation that we observed early after LCMV Cl13 infection in IL-27R-deficient mice. Together these data highlight the critical role of IL-27 in enabling optimal anti-viral immunity early and late after infection with a systemic persistent virus and suggest that a previously unrecognized positive feedback-loop mediated by IL-27 in pDCs might be involved in this process.
Ling GS, Crawford G, Buang N, et al., 2018, C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism, Science, Vol: 360, Pages: 558-563, ISSN: 0036-8075
Deficiency of C1q, the initiator of the complement classical pathway, is associated with the development of systemic lupus erythematosus (SLE). Explaining this association in terms of abnormalities in the classical pathway alone remains problematic because C3 deficiency does not predispose to SLE. Here, using a mouse model of SLE, we demonstrate that C1q, but not C3, restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8+ T cells, which can themselves propagate autoimmunity. C1q deficiency also triggers an exuberant effector CD8+ T cell response to chronic viral infection leading to lethal immunopathology. These data establish a link between C1q and CD8+ T cell metabolism and may explain how C1q protects against lupus, with implications for the role of viral infections in the perpetuation of autoimmunity.
Johnson JR, Harker JA, 2017, Allergic Airway Disease: More than Meets the IgE?, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 57, Pages: 631-632, ISSN: 1044-1549
Greczmiel U, Kräutler NJ, Pedrioli A, et al., 2017, Sustained T follicular helper cell response is essential for control of chronic viral infection., Science Immunology, Vol: 2, ISSN: 2470-9468
During chronic viral infections, both CD8 and CD4 T cell responses are functionally compromised. Alongside exhaustion of CD8 T cells during chronic viral infections, it has also been documented that the CD4 T cells have an increased propensity to differentiate toward CXCR5+ T follicular helper cell (TFH) lineage. Whether these TFH cells contribute to the immune response to chronic viral infection has remained unclear. Using chronic lymphocytic choriomeningitis virus (LCMV) infection in conjunction with an in vivo system where TFH cells can be conditionally ablated, we have established that these TFH cells do in fact play an important protective function. Specifically, we demonstrate that these TFH cells are essential for the late emergence of neutralizing LCMV-specific antibodies that keep viral titers in check and ultimately allow mice to clear the virus. By supporting the generation of neutralizing antibodies, we show that sustained activity of TFH cells promotes control of the chronic infection in face of exhausted CD8 T cell responses.
Peiró T, Patel DF, Akthar S, et al., 2017, Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection, Thorax, Vol: 73, Pages: 546-556, ISSN: 1468-3296
Background Alveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1β release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed.Methods Mice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody.Results Influenza elicited a robust IL-1β release that correlated (r=0.6849; p<0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1β during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1β in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1β from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils.Conclusions Neutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.
Pyle CJ, Uwadiae FI, Swieboda DP, et al., 2017, Early IL-6 signalling promotes IL-27 dependent maturation of regulatory T cells in the lungs and resolution of viral immunopathology., PLoS Pathogens, Vol: 13, ISSN: 1553-7366
Interleukin-6 is a pleiotropic, pro-inflammatory cytokine that can promote both innate and adaptive immune responses. In humans with respiratory virus infections, such as Respiratory Syncytial Virus (RSV), elevated concentrations of IL-6 are associated with more severe disease. In contrast the polymorphisms in the Il6 promoter which favour lower IL-6 production are associated with increased risk of both RSV and Rhinovirus infections. To determine the precise contribution of IL-6 to protection and pathology we used murine models of respiratory virus infection. RSV infection resulted in increased IL-6 production both in the airways and systemically which remained heightened for at least 2 weeks. IL-6 depletion early, but not late, during RSV or Influenza A virus infection resulted in significantly increased disease associated with an influx of virus specific TH1 and cytotoxic CD8+ T cells, whilst not affecting viral clearance. IL-6 acted by driving production of the immunoregulatory cytokine IL-27 by macrophages and monocytes, which in turn promoted the local maturation of regulatory T cells. Concordantly IL-27 was necessary to regulate TH1 responses in the lungs, and sufficient to limit RSV induced disease. Overall we found that during respiratory virus infection the prototypic inflammatory cytokine IL-6 is a critical anti-inflammatory regulator of viral induced immunopathology in the respiratory tract through its induction of IL-27.
Varricchi G, Harker J, Borriello F, et al., 2016, T follicular helper (Tfh ) cells in normal immune responses and in allergic disorders., Allergy, Vol: 71, Pages: 1086-1094, ISSN: 0105-4538
Follicular helper T cells (Tfh ) are located within germinal centers of lymph nodes. Cognate interaction between Tfh , B cells, and IL-21 drives B cells to proliferate and differentiate into plasma cells thereby leading to antibody production. Tfh cells and IL-21 are involved in infectious and autoimmune diseases, immunodeficiencies, vaccination, and cancer. Human peripheral blood CXCR5(+) CD4(+) T cells comprise different subsets of Tfh -like cells. Despite the importance of the IgE response in the pathogenesis of allergic disorders, little is known about the role of follicular and blood Tfh cells and IL-21 in human and experimental allergic disease. Here, we review recent advances regarding the phenotypic and functional characteristics of both follicular and blood Tfh cells and of the IL-21/IL-21R system in the context of allergic disorders.
Taylor A, Harker JA, Chanthong K, et al., 2016, Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8+ cytolytic T cell responses, Immunity, Vol: 44, Pages: 274-286, ISSN: 1097-4180
Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8+ T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8+ cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8+ CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8+ OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.
Lloyd CM, Harker JA, 2016, Location, Location, Location: Localized Memory Cells Take Residence in the Allergic Lung, IMMUNITY, Vol: 44, Pages: 13-15, ISSN: 1074-7613
Harker J, Wong KA, Dolgoter A, et al., 2015, Cell-intrinsic gp130 Signaling on CD4+ T cells Shapes Long-lasting Antiviral Immunity, Journal of Immunology, ISSN: 1550-6606
The interleukin-6 (IL-6) cytokine family utilizes the common signal transduction molecule gp130, which can mediate a diverse range of outcomes. To clarify the role of gp130 signaling in vivo during acute viral infection we infected Cd4-cre Il6stfl/fl 4 mice, in which gp130 is conditionally ablated in T cells, with acute lymphocytic choriomeningitis virus (LCMV). We found that by day 12, but not at day 8, post infection the number of virus specific CD4+ 6 T cellswas reduced in the absence of gp130, and this was sustained for up to 2 months post infection. Additionally gp130 deficient TFH had lower expression of Maf, IL-21 and ICOS and this was accompanied by a reduction in the proportion of germinal center B cells and plasmablasts.Remarkably, two months post-infection the proportion of IgG2a/c+ 10 memory B cells and the systemic levels of LCMV-specific IgG2 Abs were dramatically decreased, while there was a corresponding increase in IgG1+ memory B cells and virus-specific IgG1 Abs. In the same animals Gp130 deficient virus specific CD8+ T cells showed a reduced proportion of memory cells, which expressed lower levels of Tcf7, and displayed diminished recall responses on secondary infection. Mixed bone marrow chimeras revealed that the aforementioned gp130 effects on CD4+ T cells were cell-intrinsic. Overall our data show that gp130 signaling in T cells influences the quantity and quality of long lasting CD4+ T cell responses as well as CD8+ T cell and antibody mediated immunity after acute viral infection.
Zuniga EI, Macal M, Lewis GM, et al., 2015, Innate and Adaptive Immune Regulation During Chronic Viral Infections, ANNUAL REVIEW OF VIROLOGY, VOL 2, Vol: 2, Pages: 573-597, ISSN: 2327-056X
Harker JA, Dolgoter A, Wong KA, et al., 2014, T cell specific gp130 signalling orchestrates T cells and antibody responses after acute viral infection
Harker J, Dolgoter A, Lewis G, et al., 2014, Distinct and overlapping roles for cell intrinsic IL-6 and IL-27 signaling in promoting virus specific CD4+T cell numbers and function during acute and chronic viral infections, JOURNAL OF IMMUNOLOGY, Vol: 192, ISSN: 0022-1767
Harker JA, Yamaguchi Y, Culley FJ, et al., 2014, Delayed sequelae of neonatal RSV infection are dependent on cells of the innate immune system, Journal of Virology, ISSN: 0022-538X
Infection with respiratory syncytial virus (RSV) in neonatal mice leads to exacerbated disease if mice are re-infected with the same virus as adults. Both T cells and host MHC genotype contribute to this phenomenon, but the part played by innate immunity has not been defined. Since macrophages and natural killer (NK) cells play key roles in regulating inflammation during RSV infection of adult mice, we studied the role of these cells in exacerbated inflammation following neonatal RSV sensitization/adult re-infection. Compared to those undergoing primary adult infection, neonatally sensitized mice showed enhanced airway fluid levels of interleukin-6 (IL-6), interferon alpha (IFNα), CXCL1 (KC) and tumor necrosis factor alpha (TNFα) at 12-24h, and IL-4, IL-5, IFNγ and CCL11 (eotaxin) at day 4 after re-infection. Weight loss during re-infection was accompanied by an initial influx of NK cells and granulocytes into the airways and lungs, followed by T cells. NK depletion during re-infection attenuated weight loss, but did not alter T cell responses. Depleting alveolar macrophages with inhaled clodronate liposomes reduced both NK and T cell numbers and attenuated weight loss. These findings indicate a hitherto unappreciated role for the innate immune response in governing the pathogenic recall responses to RSV infection.
Tregoning JS, Wang B, McDonald JU, et al., 2013, Respiratory syncytial virus (RSV) infection during early life suppresses antibody responses by the induction of interferon gamma, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 104-104, ISSN: 0019-2805
Harker JA, Dolgoter A, Zuniga EI, 2013, Cell-Intrinsic IL-27 and gp130 Cytokine Receptor Signaling Regulates Virus-Specific CD4(+) T Cell Responses and Viral Control during Chronic Infection, IMMUNITY, Vol: 39, Pages: 548-559, ISSN: 1074-7613
Harker J, Dolgoter A, Zuniga E, 2013, Cell intrinsic gp130 signaling is vital for virus specific CD4 T cell survival and interleukin 21 production during late stages of chronic viral infection, 100th Annual Meeting of the American-Association-of-Immunologists, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Tregoning JS, Wang BL, McDonald JU, et al., 2013, Neonatal antibody responses are attenuated by interferon-gamma produced by NK and T cells during RSV infection, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 5576-5581, ISSN: 0027-8424
Yamaguchi Y, Harker JA, Wang B, et al., 2012, Preexposure to CpG Protects against the Delayed Effects of Neonatal Respiratory Syncytial Virus Infection, JOURNAL OF VIROLOGY, Vol: 86, Pages: 10456-10461, ISSN: 0022-538X
Zuniga EI, Harker JA, 2012, T-cell exhaustion due to persistent antigen: Quantity not quality?, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 42, Pages: 2285-2289, ISSN: 0014-2980
Macal M, Lewis GM, Kunz S, et al., 2012, Plasmacytoid Dendritic Cells Are Productively Infected and Activated through TLR-7 Early after Arenavirus Infection, CELL HOST & MICROBE, Vol: 11, Pages: 617-630, ISSN: 1931-3128
Harker JA, Lewis GM, Mack L, et al., 2011, Late Interleukin-6 Escalates T Follicular Helper Cell Responses and Controls a Chronic Viral Infection, SCIENCE, Vol: 334, Pages: 825-829, ISSN: 0036-8075
Telcian AG, Laza-Stanca V, Edwards MR, et al., 2011, RSV-Induced Bronchial Epithelial Cell PD-L1 Expression Inhibits CD8(+) T Cell Nonspecific Antiviral Activity, JOURNAL OF INFECTIOUS DISEASES, Vol: 203, Pages: 85-94, ISSN: 0022-1899
Tregoning JS, Yamaguchi Y, Harker JA, et al., 2010, T cell derived interferon gamma inhibits antibody responses during early life, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 52-52, ISSN: 0019-2805
Tregoning JS, Yamaguchi Y, Wang B, et al., 2010, Genetic Susceptibility to the Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Is MHC Dependent, JOURNAL OF IMMUNOLOGY, Vol: 185, Pages: 5384-5391, ISSN: 0022-1767
Lee DCP, Harker JAE, Tregoning JS, et al., 2010, CD25(+) Natural Regulatory T Cells Are Critical in Limiting Innate and Adaptive Immunity and Resolving Disease following Respiratory Syncytial Virus Infection, JOURNAL OF VIROLOGY, Vol: 84, Pages: 8790-8798, ISSN: 0022-538X
Harker JA, Lee DCP, Yamaguchi Y, et al., 2010, Delivery of Cytokines by Recombinant Virus in Early Life Alters the Immune Response to Adult Lung Infection, JOURNAL OF VIROLOGY, Vol: 84, Pages: 5294-5302, ISSN: 0022-538X
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.