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      Severe Developmental B Lymphopoietic Defects in Foxp3-Deficient Mice are Refractory to Adoptive Regulatory T Cell Therapy

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          Abstract

          The role of Foxp3-expressing regulatory T (T reg) cells in tolerance and autoimmunity is well-established. However, although of considerable clinical interest, the role of T reg cells in the regulation of hematopoietic homeostasis remains poorly understood. Thus, we analysed B and T lymphopoiesis in the scurfy (Sf) mouse model of T reg cell deficiency. In these experiments, the near-complete block of B lymphopoiesis in the BM of adolescent Sf mice was attributed to autoimmune T cells. We could exclude a constitutive lympho-hematopoietic defect or a B cell-intrinsic function of Foxp3. Efficient B cell development in the BM early in ontogeny and pronounced extramedullary B lymphopoietic activity resulted in a peripheral pool of mature B cells in adolescent Sf mice. However, marginal zone B and B-1a cells were absent throughout ontogeny. Developmental B lymphopoietic defects largely correlated with defective thymopoiesis. Importantly, neonatal adoptive T reg cell therapy suppressed exacerbated production of inflammatory cytokines and restored thymopoiesis but was ineffective in recovering defective B lymphopoiesis, probably due to a failure to compensate production of stroma cell-derived IL-7 and CXCL12. Our observations on autoimmune-mediated incapacitation of the BM environment in Foxp3-deficient mice will have direct implications for the rational design of BM transplantation protocols for patients with severe genetic deficiencies in functional Foxp3 + T reg cells.

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          Most cited references78

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          Regulatory T cell lineage specification by the forkhead transcription factor foxp3.

          Regulatory T cell-mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. Here, we present data arguing that the forkhead transcription factor Foxp3 acts as the regulatory T cell lineage specification factor and mediator of the genetic mechanism of dominant tolerance. We show that expression of Foxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity. Induction of Foxp3 expression in nonregulatory T cells does not occur during pathogen-driven immune responses, and Foxp3 deficiency does not impact the functional responses of nonregulatory T cells. Furthermore, T cell-specific ablation of Foxp3 is sufficient to induce the identical early onset lymphoproliferative syndrome observed in Foxp3-deficient mice. Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions.
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            Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.

            Naturally arising CD25(+)CD4(+) regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish transplantation tolerance. They are therefore a good target for designing ways to induce or abrogate immunological tolerance to self and non-self antigens.
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              IFNalpha activates dormant haematopoietic stem cells in vivo.

              Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNalpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFNalpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNalpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNalpha/beta receptor (IFNAR), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNalpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFNalpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil, HSCs pre-treated (primed) with IFNalpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNalpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFNalpha pathway in HSCs impairs their function, acute IFNalpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNalpha on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.
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                Author and article information

                Journal
                Front Immunol
                Front Immunol
                Front. Immun.
                Frontiers in Immunology
                Frontiers Research Foundation
                1664-3224
                19 March 2012
                05 June 2012
                2012
                : 3
                : 141
                Affiliations
                [1] 1simpleCenter for Regenerative Therapies Dresden, Technical University Dresden Dresden, Germany
                [2] 2simpleHelmholtz Centre for Infectious Research Braunschweig, Germany
                [3] 3simpleInstitute of Physiological Chemistry, Technical University Dresden Dresden, Germany
                Author notes

                Edited by: Daniel Hawiger, Saint Louis University, USA

                Reviewed by: Paulo Vieira, Institut Pasteur de Paris, France; Richard DiPaolo, Saint Louis University School of Medicine, USA

                *Correspondence: Karsten Kretschmer, Center for Regenerative Therapies Dresden, Technical University Dresden, Fetscherstr. 105, 01307 Dresden, Germany. e-mail: karsten.kretschmer@ 123456crt-dresden.de

                This article was submitted to Frontiers in Immunological Tolerance, a specialty of Frontiers in Immunology.

                Article
                10.3389/fimmu.2012.00141
                3367401
                22679447
                e401a69f-3e40-4e33-ae55-8c0a066e2787
                Copyright © 2012 Riewaldt, Düber, Boernert, Krey, Dembinski, Weiss, Garbe and Kretschmer.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 01 March 2012
                : 16 May 2012
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 93, Pages: 16, Words: 13076
                Categories
                Immunology
                Original Research

                Immunology
                b cell,scurfy,autoimmunity,lymphopoiesis,foxp3,regulatory t cell
                Immunology
                b cell, scurfy, autoimmunity, lymphopoiesis, foxp3, regulatory t cell

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