Publications by authors named "Elissa K Deenick"

58 Publications

Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency.

J Clin Immunol 2021 Apr 30. Epub 2021 Apr 30.

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

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.
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http://dx.doi.org/10.1007/s10875-021-01031-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086229PMC
April 2021

B cells: we need them now more than ever.

Authors:
Elissa K Deenick

Immunol Cell Biol 2020 07;98(6):437-438

Immunity and Inflammatory Diseases, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

The humoral immune response, that is, the production of antibodies by B cells, is a critical component of immunity to infection and underlies the protection provided by the majority of successful vaccines. This Special Feature explores some of the latest advances in understanding B cell activation and differentiation, as well as how these processes can go wrong in disease.
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http://dx.doi.org/10.1111/imcb.12348DOI Listing
July 2020

Molecular and cellular mechanisms underlying defective antibody responses.

Immunol Cell Biol 2020 07 7;98(6):467-479. Epub 2020 Jun 7.

Immunity and Inflammatory Diseases, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.

Primary immune deficiency is caused by genetic mutations that result in immune dysfunction and subsequent susceptibility to infection. Over the last decade there has been a dramatic increase in the number of genetically defined causes of immune deficiency including those which affect B-cell function. This has not only identified critical nonredundant pathways that control the generation of protective antibody responses but also revealed that immunodeficiency and autoimmunity are often closely linked. Here we explore the molecular and cellular mechanisms of these rare monogenic conditions that disrupt antibody production, which also have implications for understanding the causes of more common polygenic immune dysfunction.
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http://dx.doi.org/10.1111/imcb.12345DOI Listing
July 2020

NK Cells Regulate CD8 T Cell Mediated Autoimmunity.

Front Cell Infect Microbiol 2020 13;10:36. Epub 2020 Feb 13.

Princess Margaret Cancer Centre, Campell Family Institute for Breast Cancer Research, University Health Network (UHN), Toronto, ON, Canada.

Elucidating key factors that regulate immune-mediated pathology is critical for developing improved strategies to treat autoimmune disease and cancer. NK cells can exhibit regulatory functions against CD8 T cells following viral infection. Here we show that while low doses of lymphocytic choriomeningitis virus (LCMV-WE) can readily induce strong CD8 T cell responses and diabetes in mice expressing the LCMV glycoprotein on β-islet cells (RIP-GP mice), hyperglycemia does not occur after infection with higher doses of LCMV. High-dose LCMV infection induced an impaired CD8 T cell response, which coincided with increased NK cell activity during early time points following infection. Notably, we observed increased NKp46 expression on NK cells during infection with higher doses, which resulted in an NK cell dependent suppression of T cells. Accordingly, depletion with antibodies specific for NK1.1 as well as NKp46 deficiency ( mice) could restore CD8 T cell immunity and permitted the induction of diabetes even following infection of RIP-GP mice with high-dose LCMV. Therefore, we identify conditions where innate lymphoid cells can play a regulatory role and interfere with CD8 T cell mediated tissue specific pathology using an NKp46 dependent mechanism.
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http://dx.doi.org/10.3389/fcimb.2020.00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031256PMC
February 2020

Activated PI3Kδ breaches multiple B cell tolerance checkpoints and causes autoantibody production.

J Exp Med 2020 02;217(2)

Immunity and Inflammatory Diseases, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.

Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.
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http://dx.doi.org/10.1084/jem.20191336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041712PMC
February 2020

Immune Dysregulation and Disease Pathogenesis due to Activating Mutations in PIK3CD-the Goldilocks' Effect.

J Clin Immunol 2019 02 25;39(2):148-158. Epub 2019 Mar 25.

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

"This porridge is too hot!" she exclaimed. So, she tasted the porridge from the second bowl. "This porridge is too cold," she said. So, she tasted the last bowl of porridge. "Ahhh, this porridge is just right," she said happily and she ate it all up. While this describes the adventures of Goldilocks in the classic fairytale "The Story of Goldilocks and the Three Bears," it is an ideal analogy for the need for balanced signaling mediated by phosphatidylinositol-3-kinase (PI3K), a key signaling hub in immune cells. Either too little or too much PI3K activity is deleterious, even pathogenic-it needs to be "just right"! This has been elegantly demonstrated by the identification of inborn errors of immunity in key components of the PI3K pathway, and the impact of these mutations on immune regulation. Detailed analyses of patients with germline activating mutations in PIK3CD, as well as the parallel generation of novel murine models of this disease, have shed substantial light on the role of PI3K in lymphocyte development and differentiation, and mechanisms of disease pathogenesis resulting not only from PIK3CD mutations but genetic lesions in other components of the PI3K pathway. Furthermore, by being able to pharmacologically target PI3K, these monogenic conditions have provided opportunities for the implementation of precision medicine as a therapy, as well as to gain further insight into the consequences of modulating the PI3K pathway in clinical settings.
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http://dx.doi.org/10.1007/s10875-019-00612-9DOI Listing
February 2019

B cell-intrinsic requirement for STK4 in humoral immunity in mice and human subjects.

J Allergy Clin Immunol 2019 06 20;143(6):2302-2305. Epub 2019 Feb 20.

Immunology Division, Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.02.010DOI Listing
June 2019

Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4 T cells.

J Allergy Clin Immunol 2019 07 6;144(1):236-253. Epub 2019 Feb 6.

Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia; Clinical Immunogenomics Research Consortia Australia, Sydney, Australia. Electronic address:

Background: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8 T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4 T cells in disease pathogenesis.

Objective: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4 T-cell function.

Methods: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4 T cells and a novel murine disease model caused by overactive PI3K signaling.

Results: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (T) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human T cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a T cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4 T cells also acquired an aberrant T phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and T cells was largely CD4 T-cell extrinsic, whereas changes in cytokine production and T cell function were cell intrinsic.

Conclusion: Our studies reveal that CD4 T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.
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http://dx.doi.org/10.1016/j.jaci.2019.01.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612302PMC
July 2019

Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23.

Sci Immunol 2018 12;3(30)

Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey.

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4 T cells, including, in particular, mycobacterium-specific T1* cells (CD45RACCR6), is dependent on both IL-12 and IL-23. Last, we show that , , and have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rβ2-deficient than IL-12Rβ1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.
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http://dx.doi.org/10.1126/sciimmunol.aau6759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380365PMC
December 2018

Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency.

Nat Immunol 2018 09 20;19(9):973-985. Epub 2018 Aug 20.

La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory T1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a mice lack cDC2s, have CD4 T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory T1* cells.
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http://dx.doi.org/10.1038/s41590-018-0178-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130844PMC
September 2018

Germline-activating mutations in compromise B cell development and function.

J Exp Med 2018 08 17;215(8):2073-2095. Epub 2018 Jul 17.

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

Gain-of-function (GOF) mutations in , encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.
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http://dx.doi.org/10.1084/jem.20180010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080914PMC
August 2018

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity.

Sci Immunol 2018 06;3(24)

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France.

Heterozygosity for human () dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with DN mutations, ZNF341-deficient patients lack T helper 17 (T17) cells, have an excess of T2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the transcription-dependent autoinduction and sustained activity of STAT3.
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http://dx.doi.org/10.1126/sciimmunol.aat4956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141026PMC
June 2018

Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity.

J Allergy Clin Immunol 2019 01 22;143(1):276-291.e6. Epub 2018 May 22.

Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Sydney, Darlinghurst, Australia; CIRCA (Clinical Immunogenomics Consortia Australia), Sydney, Australia. Electronic address:

Background: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown.

Objective: Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies.

Methods: We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8 T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV.

Results: PIK3CD GOF total and EBV-specific CD8 T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8 T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70.

Conclusions: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8 T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance.
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http://dx.doi.org/10.1016/j.jaci.2018.04.030DOI Listing
January 2019

Signal Transducer and Activator of Transcription 3 Control of Human T and B Cell Responses.

Front Immunol 2018 7;9:168. Epub 2018 Feb 7.

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

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated downstream of many key cytokine receptors expressed by lymphocytes. As such, it plays a critical role in regulating B cells as well as CD4 and CD8 T cells. Patients with clinically significant immunodeficiency and immune dysregulation resulting from loss-of-function or gain-of-function mutations in STAT3 have been described. These individuals provide insight into the critical role of this transcription factor in the regulation of immune responses and the balance between effective immune protection and autoimmunity.
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http://dx.doi.org/10.3389/fimmu.2018.00168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810249PMC
March 2019

Cytokine-Mediated Regulation of Human Lymphocyte Development and Function: Insights from Primary Immunodeficiencies.

J Immunol 2017 09;199(6):1949-1958

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

Cytokine-mediated intracellular signaling pathways are fundamental for the development, activation, and differentiation of lymphocytes. These distinct processes underlie protection against infectious diseases after natural infection with pathogens or immunization, thereby providing the host with long-lived immunological memory. In contrast, aberrant cytokine signaling can also result in conditions of immune dysregulation, such as early-onset autoimmunity. Thus, balanced signals provided by distinct cytokines, and delivered to specific cell subsets, are critical for immune homeostasis. The essential roles of cytokines in human immunity have been elegantly and repeatedly revealed by the discovery of individuals with mutations in cytokine ligands, receptors, and downstream transcription factors that cause primary immunodeficiency or autoimmune conditions. In this article, we review how the discovery and characterization of such individuals has identified nonredundant, and often highly specialized, functions of specific cytokines and immune cell subsets in human lymphocyte biology, host defense against infections, and immune regulation.
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http://dx.doi.org/10.4049/jimmunol.1700842DOI Listing
September 2017

Erratum: The circulating life of a memory T-follicular helper cell.

Clin Transl Immunology 2017 May 26;6(5):e145. Epub 2017 May 26.

[This corrects the article DOI: 10.1038/cti.2017.17.].
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http://dx.doi.org/10.1038/cti.2017.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493590PMC
May 2017

The circulating life of a memory T-follicular helper cell.

Clin Transl Immunology 2017 May 19;6(5):e141. Epub 2017 May 19.

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

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http://dx.doi.org/10.1038/cti.2017.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493586PMC
May 2017

The TORC that Gets the GC Cycling.

Immunity 2017 06;46(6):974-976

Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia.

The signaling pathways regulating positive selection in germinal centers (GCs) are incompletely understood. Ersching et al. (2017) identify a critical but temporal role for the action of the kinase mechanistic target of rapamycin complex (mTORC1), which promotes key changes in GC B cells and thereby facilitates affinity maturation.
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http://dx.doi.org/10.1016/j.immuni.2017.06.003DOI Listing
June 2017

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

Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency.

J Clin Invest 2017 May 17;127(5):1991-2006. Epub 2017 Apr 17.

Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients. The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice. The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1. The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. The levels of GINS1 activity did not influence the immunological phenotype, which was uniform. Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency.
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http://dx.doi.org/10.1172/JCI90727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409070PMC
May 2017

B-cell-specific STAT3 deficiency: Insight into the molecular basis of autosomal-dominant hyper-IgE syndrome.

J Allergy Clin Immunol 2016 11 11;138(5):1455-1458.e3. Epub 2016 Jun 11.

Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Australia, Darlinghurst, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.05.018DOI Listing
November 2016

Elucidating the effects of disease-causing mutations on STAT3 function in autosomal-dominant hyper-IgE syndrome.

J Allergy Clin Immunol 2016 10 13;138(4):1210-1213.e5. Epub 2016 May 13.

Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, University of New South Wales Australia, Darlinghurst, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.04.020DOI Listing
October 2016

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

J Allergy Clin Immunol 2015 Oct 7;136(4):993-1006.e1. Epub 2015 Jul 7.

Clinical Immunology, Royal Prince Alfred Hospital, Sydney, Australia.

Background: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities.

Objective: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects.

Methods: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK.

Results: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations.

Conclusion: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.
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http://dx.doi.org/10.1016/j.jaci.2015.05.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042203PMC
October 2015

IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.

Science 2015 Aug 9;349(6248):606-613. Epub 2015 Jul 9.

La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.
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http://dx.doi.org/10.1126/science.aaa4282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668938PMC
August 2015

STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function.

J Exp Med 2015 Jun 4;212(6):855-64. Epub 2015 May 4.

Immunology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia St. Vincent's Clinical School and School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia

Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.
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http://dx.doi.org/10.1084/jem.20141992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451129PMC
June 2015

T follicular helper cells have distinct modes of migration and molecular signatures in naive and memory immune responses.

Immunity 2015 Apr 31;42(4):704-18. Epub 2015 Mar 31.

Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, 390 Victoria Street, Darlinghurst, NSW 2010, Australia. Electronic address:

B helper follicular T (Tfh) cells are critical for long-term humoral immunity. However, it remains unclear how these cells are recruited and contribute to secondary immune responses. Here we show that primary Tfh cells segregate into follicular mantle (FM) and germinal center (GC) subpopulations that display distinct gene expression signatures. Restriction of the primary Tfh cell subpopulation in the GC was mediated by downregulation of chemotactic receptor EBI2. Following collapse of the GC, memory T cells persisted in the outer follicle where they scanned CD169(+) subcapsular sinus macrophages. Reactivation and intrafollicular expansion of these follicular memory T cells in the subcapsular region was followed by their extrafollicular dissemination via the lymphatic flow. These data suggest that Tfh cells integrate their antigen-experience history to focus T cell help within the GC during primary responses but act rapidly to provide systemic T cell help after re-exposure to the antigen.
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http://dx.doi.org/10.1016/j.immuni.2015.03.002DOI Listing
April 2015

Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.

Science 2014 Sep 11;345(6204):1623-1627. Epub 2014 Sep 11.

Instituto de Medicina Integral Prof. Fernando Figueira-IMIP, 50070 Recife-PE, Brazil.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.
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http://dx.doi.org/10.1126/science.1255904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371526PMC
September 2014

STAT3 is a central regulator of lymphocyte differentiation and function.

Curr Opin Immunol 2014 Jun 6;28:49-57. Epub 2014 Mar 6.

Immunology and Immunodeficiency Group, Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW, Australia. Electronic address:

Signalling in lymphocytes through cytokine receptors is critical for their development, activation and differentiation into effector cells that mediate protection against pathogens and provide the host with protective immunological memory. The essential role of cytokine signalling has been established not only by the generation and examination of gene-targeted mice, but also 'Experiments of Nature' whereby monogenic mutations cause primary immunodeficient conditions characterised by impaired immunity to infectious diseases due to compromised lymphocyte function. Mutations in STAT3 cause autosomal dominant hyper-IgE syndrome. Here, we will review how the study of STAT3-deficient individuals has revealed non-redundant functions of STAT3 and specific cytokines in human lymphocyte biology, and have delineated mechanisms underlying the distinct clinical features of autosomal dominant hyper-IgE syndrome.
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http://dx.doi.org/10.1016/j.coi.2014.01.015DOI Listing
June 2014