Publications by authors named "Cecile King"

44 Publications

Dual Nature of Type I Interferons in SARS-CoV-2-Induced Inflammation.

Trends Immunol 2021 04 12;42(4):312-322. Epub 2021 Feb 12.

Department of Immunology, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, Department of Medicine, UNSW, Sydney, NSW 2010, Australia.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ability of our cells to secrete type I interferons (IFN-Is) is essential for the control of virus replication and for effective antiviral immune responses; for this reason, viruses have evolved the means to antagonize IFN-I. Inhibition of IFN-I production is pronounced in SARS-CoV-2 infection, which can impair the adaptive immune response and exacerbate inflammatory disease at late stages of infection. However, therapeutic boosting of IFN-I offers a narrow time window for efficacy and safety. Here, we discuss how limits placed on IFN-I by SARS-CoV-2 shape the immune response and whether this might be countered with therapeutic approaches and vaccine design.
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http://dx.doi.org/10.1016/j.it.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879020PMC
April 2021

CAR NK Cell Therapy for T Follicular Helper Cells.

Authors:
Cecile King

Cell Rep Med 2020 Apr 21;1(1):100009. Epub 2020 Apr 21.

Department of Immunology, The Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia.

T follicular helper (T) cells are associated with the development of both autoimmune disease and T cell malignancies. In this issue, Reighard et al., describe the design of PD-L1 chimeric antigen receptor (CAR) NK cells that effectively target and eliminate T cells.
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http://dx.doi.org/10.1016/j.xcrm.2020.100009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659502PMC
April 2020

Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.

Nat Immunol 2019 10 18;20(10):1299-1310. Epub 2019 Sep 18.

Research School of Chemistry, The Australian National University, Canberra, Australian Capital Territory, Australia.

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.
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http://dx.doi.org/10.1038/s41590-019-0492-0DOI Listing
October 2019

β Cell Hypoxia-Inducible Factor-1α Is Required for the Prevention of Type 1 Diabetes.

Cell Rep 2019 05;27(8):2370-2384.e6

Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia. Electronic address:

The development of autoimmune disease type 1 diabetes (T1D) is determined by both genetic background and environmental factors. Environmental triggers include RNA viruses, particularly coxsackievirus (CV), but how they induce T1D is not understood. Here, we demonstrate that deletion of the transcription factor hypoxia-inducible factor-1α (HIF-1α) from β cells increases the susceptibility of non-obese diabetic (NOD) mice to environmentally triggered T1D from coxsackieviruses and the β cell toxin streptozotocin. Similarly, knockdown of HIF-1α in human islets leads to a poorer response to coxsackievirus infection. Studies in coxsackievirus-infected islets demonstrate that lack of HIF-1α leads to impaired viral clearance, increased viral load, inflammation, pancreatitis, and loss of β cell mass. These findings show an important role for β cells and, specifically, lack of β cell HIF-1α in the development of T1D. These data suggest new strategies for the prevention of T1D.
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http://dx.doi.org/10.1016/j.celrep.2019.04.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661122PMC
May 2019

CCR9 Expressing T Helper and T Follicular Helper Cells Exhibit Site-Specific Identities During Inflammatory Disease.

Front Immunol 2018 4;9:2899. Epub 2019 Jan 4.

Department of Immunology, The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

CD4 T helper (Th) cells that express the gut homing chemokine receptor CCR9 are increased in the peripheral blood of patients with inflammatory bowel disease and Sjögren's syndrome and in the inflamed lesions of autoimmune diseases that affect the accessory organs of the digestive system. However, despite the important role of the GIT in both immunity and autoimmunity, the nature of CCR9-expressing cells in GIT lymphoid organs and their role in chronic inflammatory diseases remains unknown. In this study, we analyzed the characteristics of CCR9 Th and T follicular helper (Tfh) cells in GIT associated lymphoid tissues in health, chronic inflammation and autoimmunity. Our findings reveal an association between the transcriptome and phenotype of CCR9 Th in the pancreas and CCR9 Tfh cells from GIT-associated lymphoid tissues. GIT CCR9 Tfh cells exhibited characteristics, including a Th17-like transcriptome and production of effector cytokines, which indicated a microenvironment-specific signature. Both CCR9 Tfh cells and CCR9 Th cells from GIT-associated lymphoid tissues migrated to the pancreas. The expression of CCR9 was important for migration of both subsets to the pancreas, but Tfh cells that accumulated in the pancreas had downmodulated expression of CXCR5. Taken together, the findings provide evidence that CCR9 Tfh cells and Th cells from the GIT exhibit plasticity and can accumulate in distal accessory organs of the digestive system where they may participate in autoimmunity.
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http://dx.doi.org/10.3389/fimmu.2018.02899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329311PMC
October 2019

GPR65 inhibits experimental autoimmune encephalomyelitis through CD4 T cell independent mechanisms that include effects on iNKT cells.

Immunol Cell Biol 2018 02 19;96(2):128-136. Epub 2017 Dec 19.

Immunology Division, Garvan Institute of Medical Research, Sydney, NSW, Australia.

The G protein-coupled receptor 65 (GPR65) gene has been genetically associated with several autoimmune diseases, including multiple sclerosis (MS). GPR65 is predominantly expressed in lymphoid organs and is activated by extracellular protons. In this study, we tested whether GPR65 plays a functional role in demyelinating autoimmune disease. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we found that Gpr65-deficient mice develop exacerbated disease. CD4 helper T cells are key drivers of EAE pathogenesis, however, Gpr65 deficiency in these cells did not contribute to the observed exacerbated disease. Instead, Gpr65 expression levels were found to be highest on invariant natural killer T (iNKT) cells. EAE severity in Gpr65-deficient mice was normalized in the absence of iNKT cells (CD1d-deficient mice), suggesting that GPR65 signals in iNKT cells are important for suppressing autoimmune disease. These findings provide functional support for the genetic association of GPR65 with MS and demonstrate GPR65 signals suppress autoimmune activity in EAE.
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http://dx.doi.org/10.1111/imcb.1031DOI Listing
February 2018

Cytosolic Recognition of RNA Drives the Immune Response to Heterologous Erythrocytes.

Cell Rep 2017 Nov;21(6):1624-1638

Department of Immunology, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, Department of Medicine, University of New South Wales, Sydney, NSW 2010, Australia. Electronic address:

The archetypal T cell-dependent antigen is sheep red blood cells (SRBCs), which have defined much of what we know about humoral immunity. Early studies using solubilized or sonicated SRBCs argued that the intact structure of SRBCs was important for optimal antibody responses. However, the reason for the requirement of intact SRBCs for the response to polyvalent protein antigen remained unknown. Here, we report that the immune response to SRBCs is driven by cytosolic recognition of SRBC RNA through the RIG-I-like receptor (RLR)-mitochondrial anti-viral signaling adaptor (MAVS) pathway. Following the uptake of SRBCs by antigen-presenting cells, the MAVS signaling complex governs the differentiation of both T follicular cells and antibody-producing B cells. Importantly, the involvement of the RLR-MAVS pathway precedes that of endosomal Toll-like receptor pathways, yet both are required for optimal effect.
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http://dx.doi.org/10.1016/j.celrep.2017.10.044DOI Listing
November 2017

The importance of frequent return visits and hypertension control among US young adults: a multidisciplinary group practice observational study.

J Clin Hypertens (Greenwich) 2017 Dec 19;19(12):1288-1297. Epub 2017 Sep 19.

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Young adults (aged 18 to 39 years) have the lowest hypertension control rates compared with older adults. Shorter follow-up encounter intervals are associated with faster hypertension control rates in older adults; however, optimal intervals are unknown for young adults. The study objective was to evaluate the relationship between ambulatory blood pressure encounter intervals (average number of provider visits with blood pressures over time) and hypertension control rates among young adults with incident hypertension. A retrospective analysis was conducted of patients aged 18 to 39 years (n = 2990) with incident hypertension using Kaplan-Meier survival and Cox proportional hazards analyses over 24 months. Shorter encounter intervals were associated with higher hypertension control: <1 month (91%), 1 to 2 months (76%), 2 to 3 months (65%), 3 to 6 months (40%), and >6 months (13%). Young adults with shorter encounter intervals also had lower medication initiation, supporting the effectiveness of lifestyle modifications. Sustainable interventions for timely young adult follow-up are essential to improve hypertension control in this hard-to-reach population.
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http://dx.doi.org/10.1111/jch.13096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722664PMC
December 2017

IL-2 Shapes the Survival and Plasticity of IL-17-Producing γδ T Cells.

J Immunol 2017 10 23;199(7):2366-2376. Epub 2017 Aug 23.

Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and

IL-17-producing γδ T (γδT-17) cells have proved to be an important early source of IL-17 in many inflammatory settings and are emerging as an important participant in protumor immune responses. Considering that their peripheral activation depends largely on innate signals rather than TCR ligation, it is important to understand what mechanisms exist to curb unwanted activation. Expression of the high-affinity IL-2R on γδT-17 cells prompted us to investigate a role for this cytokine. We found γδT-17 cells to be enriched, not depleted, in IL-2-deficient mice. The absence of IL-2 also resulted in higher IL-17 production and the emergence of IL-17IFN-γ double producers. Furthermore, the addition of IL-2 to in vitro cultures of sorted γδT-17 cells was able to moderate IL-17 and affect differentiation into polyfunctional cytokine-producing cells. Interestingly, the Vγ6 subset was more susceptible to the effects of IL-2 than Vγ4 γδT-17 cells. We also found that unlike other γδ T cells, γδT-17 cells do not produce IL-2, but express Blimp-1, a known transcriptional repressor of IL-2. Although IL-2 was able to induce robust proliferation of γδT-17 cells, it did not sustain viability, negatively impacting their survival via downregulation of the IL-7R. Taken together, these data indicate that IL-2 can augment the γδT-17 response in favor of short-lived effectors with limited plasticity, particularly in the presence of IL-1β and IL-23. In this way, IL-2 may act to curtail the innate-like response of γδT-17 cells upon arrival of IL-2-producing adaptive immune cells at the site of inflammation.
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http://dx.doi.org/10.4049/jimmunol.1700335DOI Listing
October 2017

Cytokine Expression by T Follicular Helper Cells.

Methods Mol Biol 2017 ;1623:95-103

Department of Immunology, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW, 2010, Australia.

T follicular helper (Tfh) cells are a specialized subset of CD4 T cells located within temporary structures known as germinal centers (GC) formed within B cell follicles of secondary lymphoid organs. In the GC, Tfh cells facilitate the production of high-affinity antibodies through secretion of effector cytokines, such as IL-21 and IL-4, and through cell-to-cell interactions. The flow cytometric-based method described here allows the detection of intracellular cytokines within the Tfh population of secondary lymphoid organs (e.g., spleen, lymph nodes, and lymphoid nodules such as Peyer's patches), enabling the study of Tfh responses to different stimuli in the context of immunity and autoimmunity.
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http://dx.doi.org/10.1007/978-1-4939-7095-7_8DOI Listing
March 2018

Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells.

Nat Commun 2017 05 12;8:15373. Epub 2017 May 12.

Immunology Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.

Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy is mediated by CD8 and NK cell activity at the tumour site, considerable efforts have focused on generating variants that expand these subsets systemically, as exemplified by IL-2/antibody complexes and 'superkines'. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25 regulatory T-cells (Tregs) and results in strong expansion of CD25 cytotoxic subsets. Surprisingly, however, such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. Instead, we report that efficacy is crucially dependent on depletion of Tregs through Fc-mediated immune effector functions. Our results underpin an unexpected mechanism of action and provide important guidance for the development of next generation IL-2 therapeutics.
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http://dx.doi.org/10.1038/ncomms15373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437307PMC
May 2017

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2.

Nat Commun 2017 03 17;8:14647. Epub 2017 Mar 17.

Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.

T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3 regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.
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http://dx.doi.org/10.1038/ncomms14647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357862PMC
March 2017

Longitudinal Impact of Smoking and Smoking Cessation on Inflammatory Markers of Cardiovascular Disease Risk.

Arterioscler Thromb Vasc Biol 2017 02 8;37(2):374-379. Epub 2016 Dec 8.

From the Department of Medicine (C.C.K., M.E.P., A.D.G., M.C.F., T.B.B., J.H.S.) and Center for Tobacco Research and Intervention (M.E.P., M.C.F., T.B.B.), University of Wisconsin School of Medicine and Public Health, Madison.

Objective: To evaluate longitudinal changes in 6 inflammatory markers that predict cardiovascular disease events among smokers making a quit attempt and to characterize their cross-sectional associations between smoking and smoking heaviness.

Approach And Results: In a longitudinal cohort study of contemporary smokers (n=1652), we evaluated (1) independent associations of smoking heaviness markers (exhaled carbon monoxide, cigarettes/d, pack-years) with inflammatory markers (C-reactive protein, D-dimer, fibrinogen, urinary F isoprostane:creatinine [F:Cr] ratio, white blood cell [WBC] count, myeloperoxidase) and (2) the effects of smoking cessation and continued smoking on these inflammatory markers after 1 year, among the 888 smokers who made an aided quit attempt as part of a randomized comparative effectiveness trial or standard care. There were strong, independent associations between smoking heaviness markers and the F:Cr ratio, WBC, and myeloperoxidase (all P<0.001), but not high-sensitivity C-reactive protein, D-dimer, or fibrinogen. Participants were mean (SD) 49.6 years old (11.6), 54% women, 34% non-white, and smoked 16.8 cigarettes/d (8.5) for 27.3 pack-years (18.6). After 1 year, the 344 successful abstainers gained more weight (4.0 [6.0] versus 0.4 [5.7] pounds; P<0.001) and had larger increases in insulin resistance scores (P=0.02) than continuing smokers. Despite these increases, abstainers had significant decreases in F:Cr ratio (P<0.001) and WBC counts (P<0.001). Changes in other markers were not related to quitting.

Conclusions: Smoking heaviness is associated with increased F:Cr ratio, myeloperoxidase, and WBC counts. Cessation improves the F:Cr ratio and WBC counts independent of weight change, suggesting reduced inflammation related to less oxidant stress.
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http://dx.doi.org/10.1161/ATVBAHA.116.308728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269476PMC
February 2017

CD45-mediated control of TCR tuning in naïve and memory CD8 T cells.

Nat Commun 2016 11 14;7:13373. Epub 2016 Nov 14.

Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.

Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8 T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8 T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens.
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http://dx.doi.org/10.1038/ncomms13373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114568PMC
November 2016

IL-27 Directly Enhances Germinal Center B Cell Activity and Potentiates Lupus in Sanroque Mice.

J Immunol 2016 10 12;197(8):3008-3017. Epub 2016 Sep 12.

Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;

Germinal centers (GC) give rise to high-affinity and long-lived Abs and are critical in immunity and autoimmunity. IL-27 supports GCs by promoting survival and function of T follicular helper cells. We demonstrate that IL-27 also directly enhances GC B cell function. Exposure of naive human B cells to rIL-27 during in vitro activation enhanced their differentiation into CD20CD38CD27CD95CD10 cells, consistent with the surface marker phenotype of GC B cells. This effect was inhibited by loss-of-function mutations in STAT1 but not STAT3 To extend these findings, we studied the in vivo effects of IL-27 signals to B cells in the GC-driven Roquin lupus mouse model. Il27raRoquin mice exhibited significantly reduced GCs, IgG2a(c) autoantibodies, and nephritis. Mixed bone marrow chimeras confirmed that IL-27 acts through B cell- and CD4 T cell-intrinsic mechanisms to support GCs and alter the production of pathogenic Ig isotypes. To our knowledge, our data provide the first evidence that IL-27 signals directly to B cells promote GCs and support the role of IL-27 in lupus.
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http://dx.doi.org/10.4049/jimmunol.1600652DOI Listing
October 2016

Correction: Cytokines in the Germinal Center Niche 2016, (1), 5.

Antibodies (Basel) 2016 04 27;5(2). Epub 2016 Apr 27.

Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.

The following corrections should be made to the references and bibliography of the published paper [1]:[...].
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http://dx.doi.org/10.3390/antib5020010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698849PMC
April 2016

Cytokines in the Germinal Center Niche.

Antibodies (Basel) 2016 Feb 5;5(1). Epub 2016 Feb 5.

Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.

Cytokines are small, secreted, glycoproteins that specifically affect the interactions and communications between cells. Cytokines are produced transiently and locally, acting in a paracrine or autocrine manner, and they are extremely potent, ligating high affinity cell surface receptors to elicit changes in gene expression and protein synthesis in the responding cell. Cytokines produced during the differentiation of T follicular helper (Tfh) cells and B cells within the germinal center (GC) niche play an important role in ensuring that the humoral immune response is robust, whilst retaining flexibility, during the generation of affinity matured antibodies. Cytokines produced by B cells, antigen presenting cells and stromal cells are important for the differentiation of Tfh cells and Tfh cell produced cytokines act both in an autocrine fashion to firm Tfh cell differentiation and in a paracrine fashion to support the differentiation of memory B cells and plasma cells. In this review, we discuss the role of cytokines during the GC reaction with a particular focus on the influence of cytokines on Tfh cells.
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http://dx.doi.org/10.3390/antib5010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698856PMC
February 2016

IL-21 and IL-4 Collaborate To Shape T-Dependent Antibody Responses.

J Immunol 2015 Dec 21;195(11):5123-35. Epub 2015 Oct 21.

Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia

The selection of affinity-matured Ab-producing B cells is supported by interactions with T follicular helper (Tfh) cells. In addition to cell surface-expressed molecules, cytokines produced by Tfh cells, such as IL-21 and IL-4, provide B cell helper signals. In this study, we analyze how the fitness of Th cells can influence Ab responses. To do this, we used a model in which IL-21R-sufficient (wild-type [WT]) and -deficient (Il21r(-/-)) Ag-specific Tfh cells were used to help immunodeficient Il21r(-/-) B cells following T-dependent immunization. Il21r(-/-) B cells that had received help from WT Tfh cells, but not from Il21r(-/-) Tfh cells, generated affinity-matured Ab upon recall immunization. This effect was dependent on IL-4 produced in the primary response and associated with an increased fraction of memory B cells. Il21r(-/-) Tfh cells were distinguished from WT Tfh cells by a decreased frequency, reduced conjugate formation with B cells, increased expression of programmed cell death 1, and reduced production of IL-4. IL-21 also influenced responsiveness to IL-4 because expression of both membrane IL-4R and the IL-4-neutralizing soluble (s)IL-4R were reduced in Il21r(-/-) mice. Furthermore, the concentration of sIL-4R was found to correlate inversely with the amount of IgE in sera, such that the highest IgE levels were observed in Il21r(-/-) mice with the least sIL-4R. Taken together, these findings underscore the important collaboration between IL-4 and IL-21 in shaping T-dependent Ab responses.
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http://dx.doi.org/10.4049/jimmunol.1501463DOI Listing
December 2015

Regulatory T cells prevent inducible BALT formation by dampening neutrophilic inflammation.

J Immunol 2015 May 25;194(9):4567-76. Epub 2015 Mar 25.

School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia; Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Queensland 4006, Australia

Inducible BALT (iBALT) can amplify pulmonary or systemic inflammatory responses to the benefit or detriment of the host. We took advantage of the age-dependent formation of iBALT to interrogate the underlying mechanisms that give rise to this ectopic, tertiary lymphoid organ. In this study, we show that the reduced propensity for weanling as compared with neonatal mice to form iBALT in response to acute LPS exposure is associated with greater regulatory T cell expansion in the mediastinal lymph nodes. Ab- or transgene-mediated depletion of regulatory T cells in weanling mice upregulated the expression of IL-17A and CXCL9 in the lungs, induced a tissue neutrophilia, and increased the frequency of iBALT to that observed in neonatal mice. Remarkably, neutrophil depletion in neonatal mice decreased the expression of the B cell active cytokines, a proliferation-inducing ligand and IL-21, and attenuated LPS-induced iBALT formation. Taken together, our data implicate a role for neutrophils in lymphoid neogenesis. Neutrophilic inflammation is a common feature of many autoimmune diseases in which iBALT are present and pathogenic, and hence the targeting of neutrophils or their byproducts may serve to ameliorate detrimental lymphoid neogenesis in a variety of disease contexts.
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http://dx.doi.org/10.4049/jimmunol.1400909DOI Listing
May 2015

IL-21 contributes to fatal inflammatory disease in the absence of Foxp3+ T regulatory cells.

J Immunol 2014 Feb 20;192(4):1404-14. Epub 2014 Jan 20.

Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;

The cytokine IL-21 has been shown to influence immune responses through both costimulatory effects on effector T cells and opposing inhibitory effects on T regulatory cells (Tregs). To distinguish the effect of IL-21 on the immune system from that of its effect on Tregs, we analyzed the role of IL-21/IL-21R signaling in mice made genetically deficient in IL-2, which exhibit a deficit in IL-2-dependent Foxp3 regulatory T cells and suffer from a fatal multiorgan inflammatory disease. Our findings demonstrate that in the absence of IL-21/IL-21R signaling, Il2(-/-) mice retained a deficiency in Tregs yet exhibited a reduced and delayed inflammatory disease. The improved health of Il2(-/-)Il21r(-/-) mice was reflected in reduced pancreatitis and hemolytic anemia and this was associated with distinct changes in lymphocyte effector populations, including the reduced expansion of both T follicular helper cells and Th17 cells and a compensatory increase in IL-22 in the absence of IL-21R. IL-21/IL-21R interactions were also important for the expansion of effector and memory CD8(+) T cells, which were critical for the development of pancreatitis in Il2(-/-) mice. These findings demonstrate that IL-21 is a major target of immune system regulation.
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http://dx.doi.org/10.4049/jimmunol.1302285DOI Listing
February 2014

IL-21-producing Th cells in immunity and autoimmunity.

J Immunol 2013 Oct;191(7):3501-6

Immunological Diseases Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010.

IL-21 is a member of the common γ-chain signaling family of cytokines. Analyses of the behavior of immune cells in response to IL-21 in vitro and studies of mice deficient in IL-21 or its receptor indicate that IL-21 has a role in lymphocyte activation, proliferation, differentiation, and survival. IL-21-producing CD4(+) Th cells constitute a broad array of helper subtypes including T follicular helper cells and Th17 cells. Both autocrine and paracrine utilization of IL-21 contributes to the overall signal transduction pathways of the Ag receptor to influence the growth and survival of lymphocytes. The redundancy that IL-21 exhibits in lymphoid organs during immune responses is in stark contrast to the evidence that pharmacological neutralization of this cytokine can halt inflammation in nonlymphoid organs where IL-21 becomes the dominant voice.
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http://dx.doi.org/10.4049/jimmunol.1301454DOI Listing
October 2013

Interleukin-27 signaling promotes immunity against endogenously arising murine tumors.

PLoS One 2013 12;8(3):e57469. Epub 2013 Mar 12.

Immunological Diseases Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

Interleukin-27 (IL-27) is a pleiotropic cytokine but its immunosuppressive effects predominate during many in vivo immunological challenges. Despite this, evidence from tumor cell line transfer models suggested that IL-27 could promote immune responses in the tumor context. However, the role of IL-27 in immunity against tumors that develop in situ and in tumor immunosurveillance remain undefined. In this study, we demonstrate that tumor development and growth are accelerated in IL-27 receptor α (Il27ra)-deficient mice. Enhanced tumor growth in both carcinogen-induced fibrosarcoma and oncogene-driven mammary carcinoma was associated with decreased interferon-γ production by CD4 and CD8 T cells and increased numbers of regulatory T-cells (Treg). This is the first study to show that IL-27 promotes protective immune responses against endogenous tumors, which is critical as the basis for future development of an IL-27 based therapeutic agent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057469PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595259PMC
September 2013

Emerging cellular networks for regulation of T follicular helper cells.

Trends Immunol 2012 Feb 28;33(2):59-65. Epub 2011 Dec 28.

Department of Immunology, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.

The cellular networks that regulate humoral immune responses have been a focus of research over the past three decades. Studies have shown that inhibition of immune responses can be attributed to both suppressor T cells and B cells. More recently, T follicular helper (Tfh) cells have been identified as a target of immune regulation. Tfh cells are a subset of highly activated T helper cells specialized for providing cognate help to B cells during germinal center reactions. In this review, we describe emerging evidence for cellular networks that alter Tfh cell phenotype and function and regulate antibody production during the germinal center reaction. We discuss how these new findings influence our understanding of Tfh cells.
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http://dx.doi.org/10.1016/j.it.2011.11.006DOI Listing
February 2012

A fine romance: T follicular helper cells and B cells.

Authors:
Cecile King

Immunity 2011 Jun;34(6):827-9

Department of Immunology, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.

T follicular helper (Tfh) cells help B cells to generate affinity-matured antibodies. Three papers in this issue of Immunity (Choi et al., 2011; Kerfoot et al., 2011; Kitano et al., 2011) provide information about the reciprocal relationship between B cells and Tfh cells.
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http://dx.doi.org/10.1016/j.immuni.2011.06.007DOI Listing
June 2011

Defective differentiation of regulatory FoxP3+ T cells by small-intestinal dendritic cells in patients with type 1 diabetes.

Diabetes 2011 Aug 6;60(8):2120-4. Epub 2011 Jun 6.

Experimental Diabetes Unit, Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.

Objective: The gut environment modulates the pathogenesis of type 1 diabetes (T1D), but how it affects autoimmunity toward pancreatic β-cells, a self-tissue located outside the intestine, is still unclear. In the small intestine, lamina propria dendritic cells (LPDCs) induce peripheral differentiation of FoxP3(+) regulatory T (Treg) cells. We tested the hypothesis that the intestinal milieu impinges on human T1D by affecting differentiation of FoxP3(+) Treg cells.

Research Design And Methods: We collected duodenal biopsies of 10 T1D patients, 16 healthy subjects, and 20 celiac individuals and performed a fluorescent-activated cell sorter analysis to measure percentages of various immune cell subsets, including CD4(+) and CD8(+) T cells, NK cells, γδ T cells, CD103(+)CD11c(+) LPDCs, and CD4(+)CD25(+)FoxP3(+)CD127(-) Treg cells. In parallel, we assessed the tolerogenic function (i.e., capacity to induce differentiation of FoxP3(+) Treg cells) by LPDCs of T1D patients and control subjects.

Results: Our analysis revealed a significant reduction in the percentage of intestinal CD4(+)CD25(+)FoxP3(+)CD127(-) Treg cells in T1D patients compared with healthy subjects (P = 0.03) and celiac individuals (P = 0.003). In addition, we found that LPDCs from T1D patients completely lacked their tolerogenic function; they were unable to convert CD4(+)CD25(-) T cells into CD4(+)CD25(+)FoxP3(+)CD127(-) Treg cells.

Conclusions: Our data indicate that T1D patients have a reduced number of intestinal FoxP3(+) Treg cells as a result of their defective differentiation in the gut. These findings suggest that intestinal immune regulation is not only calibrated to tolerate commensal bacteria and food components but also is instrumental in maintaining immune tolerance toward pancreatic β-cells and preventing T1D.
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http://dx.doi.org/10.2337/db10-1201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142071PMC
August 2011

Calcineurin-dependent negative regulation of CD94/NKG2A expression on naive CD8+ T cells.

Blood 2011 Jul 3;118(1):116-28. Epub 2011 May 3.

Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.

Immune responses lead to expression of immunoregulatory molecules on T cells, including natural killer (NK) receptors, such as CD94/NKG2A on CD8(+) T cells; these receptors restrain CD8(+) responses, thereby preventing T-cell exhaustion in chronic infections and limiting immunopathology. Here, we examined the requirements for inducing CD94/NKG2A on T cells responding to antigen. In vitro, moderate induction of CD94/NKG2A expression occurred after exposure of naive CD8(+) (but not CD4(+)) cells to CD3 ligation or specific peptide. Surprisingly, expression was inhibited by CD28/B7 costimulation. Such inhibition applied only to CD94/NKG2A and not other NK receptors (NKG2D) and was mediated by IL-2. Inhibition by IL-2 occurred via a NFAT cell-independent component of the calcineurin pathway, and CD94/NKG2A induction was markedly enhanced in the presence of calcineurin blockers, such as FK506 or using calcineurin-deficient T cells, both in vitro and in vivo. In addition to CD28-dependent inhibition by IL-2, CD94/NKG2A expression was impaired by several other cytokines (IL-4, IL-23, and transforming growth factor-β) but enhanced by others (IL-6, IL-10, and IL-21). The complex interplay between these various stimuli may account for the variable expression of CD94/NKG2A during responses to different pathogens in vivo.
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http://dx.doi.org/10.1182/blood-2010-11-317396DOI Listing
July 2011

A subset of interleukin-21+ chemokine receptor CCR9+ T helper cells target accessory organs of the digestive system in autoimmunity.

Immunity 2011 Apr;34(4):602-15

Department of Immunology, The Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.

This study describes a CD4+ T helper (Th) cell subset marked by coexpression of the cytokine interleukin 21 (IL-21) and the gut-homing chemokine receptor CCR9. Although CCR9+ Th cells were observed in healthy mice and humans, they were enriched in the inflamed pancreas and salivary glands of NOD mice and in the circulation of Sjögren's syndrome patients. CCR9+ Th cells expressed large amounts of IL-21, inducible T cell costimulator (ICOS), and the transcription factors Bcl6 and Maf, and also supported antibody production from B cells, thereby resembling T follicular B helper (Tfh) cells. However, in contrast to Tfh cells, CCR9+ Th cells displayed limited expression of CXCR5 and the targets of CCR9+ Th cells were CD8+ T cells whose responsiveness to IL-21 was necessary for the development of diabetes. Thus, CCR9+ Th cells are a subset of IL-21-producing T helper cells that influence regional specification of autoimmune diseases that affect accessory organs of the digestive system.
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http://dx.doi.org/10.1016/j.immuni.2011.01.021DOI Listing
April 2011

The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions.

PLoS One 2011 Feb 25;6(2):e17049. Epub 2011 Feb 25.

Department of Immunology, The Scripps Research Institute, La Jolla, California, United States of America.

In the NOD mouse, the incidence of type-1 diabetes is thought to be influenced by the degree of cleanliness of the mouse colony. Studies collectively demonstrate that exposure to bacterial antigen or infection in the neonatal period prevents diabetes [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], supporting the notion that immunostimulation can benefit the maturation of the postnatal immune system [11]. A widely accepted extrapolation from this data has been the notion that NOD mice maintained under germ-free conditions have an increased incidence of diabetes. However, evidence supporting this influential concept is surprisingly limited [12]. In this study, we demonstrate that the incidence of diabetes in female NOD mice remained unchanged under germ-free conditions. By contrast, a spontaneous monoculture with a gram-positive aerobic spore-forming rod delayed the onset and reduced the incidence of diabetes. These findings challenge the view that germ-free NOD mice have increased diabetes incidence and demonstrate that modulation of intestinal microbiota can prevent the development of type-1 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017049PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045412PMC
February 2011

Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models.

Diabetes 2011 Mar;60(3):867-75

Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.

Objective: Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21-targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models.

Research Design And Methods: NOD mice were treated with IL-21R/Fc, an IL-21-neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R-deficient mice was also assessed.

Results: Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21-responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection.

Conclusions: Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes.
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http://dx.doi.org/10.2337/db10-1157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046847PMC
March 2011

IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells.

J Exp Med 2010 Dec 22;207(13):2895-906. Epub 2010 Nov 22.

Garvan Institute of Medical Research, Darlinghurst, Sydney NSW 2010, Australia.

Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (T(FH)) cells. T(FH) cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of T(FH) cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of T(FH) cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4(+) T cells and the expression of T(FH) cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and T(FH) cell survival in a T cell-intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra(-/-) mice. Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses.
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http://dx.doi.org/10.1084/jem.20100064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005229PMC
December 2010