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      LEF-1 and TCF-1 orchestrate T follicular helper cell differentiation by regulating differentiation circuits upstream of Bcl6

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          Abstract

          T follicular helper (T FH) cells are specialized effector CD4 + T cells that help B cells develop germinal centers and memory. However, the transcription factors that regulate T FH differentiation remain incompletely understood. Here we report that selective loss of either Lef1 (LEF-1) or Tcf7 (TCF-1) resulted in T FH defects, while deletion of Lef1 and Tcf7 severely impaired T FH differentiation and germinal centers. Forced expression of LEF-1 enhanced T FH differentiation. LEF-1 and TCF-1 coordinated T FH differentiation by two general mechanisms. First, they established the responsiveness of naïve CD4 + T cells to T FH signals. Second, they promoted early T FH differentiation via the multipronged approach of sustaining expression of IL-6Rα and gp130, enhancing ICOS expression, and promoting expression of Bcl6.

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          Most cited references29

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          Germinal center selection and the development of memory B and plasma cells.

          A hallmark of adaptive immune responses is the generation of long-lived protection after primary exposure to a pathogen. In humoral responses, this protection stems from a combination of sustained antibody titers and long-lived memory B cells (MBCs), with the former deriving from long-lived plasma cells (PCs). Both types of cell are thought to primarily derive from the germinal center (GC), a unique structure that forms during the immune response to many types of antigenic stimuli. GCs are seeded by antigen-specific B and T cells that were previously activated in the early stages of the response. The GC does not directly or immediately generate effector function; rather, it is a site of intense B-cell proliferation and cell death. GC B cells undergo both somatic hypermutation and isotype switch, and a Darwinian process very efficiently selects B cells with higher fitness for survival and expansion. GC B cells adopt a unique activation and transcriptional state, and the cells become poised to differentiate to either MBCs or PCs. Despite this general understanding of the events in the GC, the mechanisms that control both affinity selection as well as differentiation have not been well worked out. In this review, we address what is known about what determines whether GC B cells become MBCs or PCs. This is discussed in the broader context of the origins of both cell types, whether from the GC or potentially other sources. We present a model encompassing recent data from several laboratories including our own that suggests that the GC undergoes a temporal switch that alters the nature of its output from MBCs to PCs as the response progresses. We will discuss B-cell receptor signaling in the GC as it relates to potential mechanisms for affinity-based selection during the reaction. © 2012 John Wiley & Sons A/S.
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            Transcription factor Achaete-Scute homologue 2 initiates T follicular helper cell development

            In immune responses, activated T cells migrate to B cell follicles and develop to T follicular helper (Tfh) cells, a new subset of CD4+ T cells specialized in providing help to B lymphocytes in the induction of germinal centers 1,2 . Although Bcl6 has been shown to be essential in Tfh cell function, it may not regulate the initial migration of T cells 3 or the induction of Tfh program as exampled by C-X-C chemokine receptor type 5 (CXCR5) upregulation 4 . Here, we show that Achaete-Scute homologue 2 (Ascl2), a basic helix-loop-helix (bHLH) transcription factor 5 , is selectively upregulated in its expression in Tfh cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6 and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro and accelerates T cell migration to the follicles and Tfh cell development in vivo. Genome-wide analysis indicates that Ascl2 directly regulates Tfh-related genes while inhibits expression of Th1 and Th17 genes. Acute deletion of Ascl2 as well as blockade of its function with the Id3 protein in CD4+ T cells results in impaired Tfh cell development and the germinal center response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances Tfh cell generation. Thus, Ascl2 directly initiates Tfh cell development.
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              Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation.

              Bcl6 is required for CD4 T cell differentiation into T follicular helper cells (Tfh). In this study, we examined the role of IL-6 in early processes of in vivo Tfh differentiation, because the timing and mechanism of action of IL-6 in Tfh differentiation have been controversial in vivo. We found that early Bcl6(+)CXCR5(+) Tfh differentiation was severely impaired in the absence of IL-6; however, STAT3 deficiency failed to recapitulate that defect. IL-6R signaling activates the transcription factor STAT1 specifically in CD4 T cells. Strikingly, we found that STAT1 activity was required for Bcl6 induction and early Tfh differentiation in vivo. IL-6 mediated STAT3 activation is important for downregulation of IL-2Rα to limit Th1 cell differentiation in an acute viral infection. Thus, IL-6 signaling is a major early inducer of the Tfh differentiation program unexpectedly mediated by both STAT3 and STAT1 transcription factors.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature immunology
                1529-2908
                1529-2916
                17 June 2015
                27 July 2015
                September 2015
                01 March 2016
                : 16
                : 9
                : 980-990
                Affiliations
                [1 ]Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
                [2 ]Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
                [3 ]Interdiscipilinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
                [4 ]Department of Physics, The George Washington University, Washington DC, 20052
                [5 ]Section on Cellular and Developmental Biology, NICHD, NIH, Bethesda, MD 20892
                Author notes
                [* ]Corresponding authors: Shane Crotty. shane@ 123456lji.org And Hai-Hui Xue. hai-hui-xue@ 123456uiowa.edu
                [^]

                These authors contributed equally

                Article
                NIHMS700724
                10.1038/ni.3226
                4545301
                26214741
                a04d78f8-71f1-497a-89bd-e4fab3ee5172

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                Article

                Immunology
                lymphoid enhancer factor (lef)-1,t cell factor (tcf)-1,il-6 receptor alpha (il-6rα),il-6 signal transducer (gp130),inducible costimulator (icos),b cell lymphoma 6 (bcl6),prdm1,blimp1

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