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      B cell–intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans

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      1 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 4 , 3 , 4 , 1 , 2 , 1 , 2 , 5 , 5 , 6 , 7 , 8 , 9 , 1 , 2 , 10 , 11 , 12 , 13 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 1 , 2 , 21 , 5 , 6 , 3 , 4 , 22 , 1 , 2 ,
      The Journal of Experimental Medicine
      The Rockefeller University Press

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          Abstract

          Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.

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          Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.

          Induced overexpression of AID in CH12F3-2 B lymphoma cells augmented class switching from IgM to IgA without cytokine stimulation. AID deficiency caused a complete defect in class switching and showed a hyper-IgM phenotype with enlarged germinal centers containing strongly activated B cells before or after immunization. AID-/- spleen cells stimulated in vitro with LPS and cytokines failed to undergo class switch recombination although they expressed germline transcripts. Immunization of AID-/- chimera with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma-globulin induced neither accumulation of mutations in the NP-specific variable region gene nor class switching. These results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation.
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            The JAK-STAT signaling pathway: input and output integration.

            Universal and essential to cytokine receptor signaling, the JAK-STAT pathway is one of the best understood signal transduction cascades. Almost 40 cytokine receptors signal through combinations of four JAK and seven STAT family members, suggesting commonality across the JAK-STAT signaling system. Despite intense study, there remain substantial gaps in understanding how the cascades are activated and regulated. Using the examples of the IL-6 and IL-10 receptors, I will discuss how diverse outcomes in gene expression result from regulatory events that effect the JAK1-STAT3 pathway, common to both receptors. I also consider receptor preferences by different STATs and interpretive problems in the use of STAT-deficient cells and mice. Finally, I consider how the suppressor of cytokine signaling (SOCS) proteins regulate the quality and quantity of STAT signals from cytokine receptors. New data suggests that SOCS proteins introduce additional diversity into the JAK-STAT pathway by adjusting the output of activated STATs that alters downstream gene activation.
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              A fundamental role for interleukin-21 in the generation of T follicular helper cells.

              T cell help to B cells is a fundamental property of adaptive immunity, yet only recently have many of the cellular and molecular mechanisms of T cell help emerged. T follicular helper (Tfh) cells are the CD4(+) T helper cells that provide cognate help to B cells for high-affinity antibody production in germinal centers (GC). Tfh cells produce interleukin-21 (IL-21), and we show that IL-21 was necessary for GC formation. However, the central role of IL-21 in GC formation reflected its effects on Tfh cell generation rather than on B cells. Expression of the inducible costimulator (ICOS) was necessary for optimal production of IL-21, indicative of interplay between these two Tfh cell-expressed molecules. Finally, we demonstrate that IL-21's costimulatory capacity for T helper cell differentiation operated at the level of the T cell receptor signalosome through Vav1, a signaling molecule that controls T cell helper function. This study reveals a previously unappreciated role for Tfh cells in the formation of the GC and isotype switching through a CD4(+) T cell-intrinsic requirement for IL-21.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                18 January 2010
                : 207
                : 1
                : 155-171
                Affiliations
                [1 ]Immunology Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
                [2 ]St. Vincent's Clinical School, University of New South Wales, Darlinghurst, NSW 2010, Australia
                [3 ]Australian National University Medical School, Canberra, ACT 2600, Australia
                [4 ]John Curtin School of Medical Research, Canberra, ACT 2600, Australia
                [5 ]Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U550, Necker Medical School, University Paris Descartes, 75015 Paris, France
                [6 ]Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065
                [7 ]Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Melbourne, VIC 3052, Australia
                [8 ]Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Parkville, VIC 3053, Australia
                [9 ]Department of Paediatrics and Child Health, Royal Children's Hospital Brisbane, Brisbane, QLD 4006, Australia
                [10 ]Department of Clinical Immunology, Royal Perth Hospital, Perth, WA 6000, Australia
                [11 ]School of Pathology and Laboratory Medicine, University of Western Australia, Perth, WA 6000, Australia
                [12 ]Department of Pediatrics, Hadassah University Hospital, Ein-Kerem, 91120 Jerusalem, Israel
                [13 ]Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
                [14 ]Novel Primary Immunodeficiency and Infectious Diseases Program, Department of Pediatrics, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia
                [15 ]Department of Pediatric Pneumology and Immunology, Charité, Humboldt University of Berlin, 10117 Berlin, Germany
                [16 ]Department of Pediatrics, University Clinic Carl Gustav Carus, 01307 Dresden, Germany
                [17 ]University of Manchester, Royal Manchester Children's Hospital, Manchester M13 9WP, England, UK
                [18 ]Department of Human Immunology, SA Pathology, Adelaide, SA 5000, Australia
                [19 ]Department of Immunology, Concord Hospital, Concord, NSW 2139, Australia
                [20 ]Department of Immunology, Children's Hospital at Westmead, Westmead, NSW 2145, Australia
                [21 ]Department of Immunology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW 2145, Australia
                [22 ]Department of Immunology, The Canberra Hospital, Canberra, ACT 2606, Australia
                Author notes
                CORRESPONDENCE Stuart Tangye: s.tangye@ 123456garvan.org.au

                D.T. Avery, E.K. Deenick, and C.S. Ma contributed equally to this paper

                Article
                20091706
                10.1084/jem.20091706
                2812540
                20048285
                dc24e74b-2cf2-4086-8fdc-a4945aa9f8ff
                © 2010 Avery et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 5 August 2009
                : 9 December 2009
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                Medicine
                Medicine

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