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Author Picca, C.C.; Larkin, J. 3rd; Boesteanu, A.; Lerman, M.A.; Rankin, A.L.; Caton, A.J. url  openurl
  Title Role of TCR specificity in CD4+ CD25+ regulatory T-cell selection Type Journal Article
  Year 2006 Publication Immunol Rev Abbreviated Journal  
  Volume 212 Issue (up) Pages 74-85  
  Keywords  
  Abstract CD4+ CD25+ regulatory T cells play a crucial role in preventing autoimmune disease and can also modulate immune responses in settings such as transplantation and infection. We have developed a transgenic mouse system in which the role that T-cell receptor (TCR) specificity for self-peptides plays in the formation of CD4+ CD25+ regulatory T cells can be examined. We have shown that interactions with a single self-peptide can induce thymocytes bearing an autoreactive TCR to undergo selection to become CD4+ CD25+ regulatory T cells and that thymocytes bearing TCRs with low affinity for the selecting peptide do not appear to undergo selection into this pathway. In addition, thymocytes with identical specificity for the selecting self-peptide can undergo overt deletion versus abundant selection to become CD4+ CD25+ regulatory T cells in response to variations in expression of the selecting peptide in different lineages of transgenic mice. Finally, we have shown that CD4+ CD25+ T cells proliferate in response to their selecting self-peptide in the periphery, but these cells do not proliferate in response to lymphopenia in the absence of the selecting self-peptide. These studies are determining how the specificity of the TCR for self-peptides directs the thymic selection and peripheral expansion of CD4+ CD25+ regulatory T cells.  
  Address  
  Corporate Author Thesis  
  Publisher Place of Publication The Wistar Institute, Philadelphia, PA 19104, USA. Editor  
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  Notes Approved no  
  Call Number MRC @ kga @ Picca2006 Serial 589  
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Author Lahl, K.; Loddenkemper, C.; Drouin, C.; Freyer, J.; Arnason, J.; Eberl, G.; Hamann, A.; Wagner, H.; Huehn, J.; Sparwasser, T. url  openurl
  Title Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease Type Journal Article
  Year 2007 Publication J Exp Med Abbreviated Journal  
  Volume Issue (up) Pages  
  Keywords  
  Abstract The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3-4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome-transgenic mice termed “depletion of regulatory T cell” (DEREG) mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3(+) T reg cells by DT injection. Ablation of Foxp3(+) T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3(+) T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3(+) T reg cells in immune reactions in vivo.  
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  Corporate Author Thesis  
  Publisher Place of Publication Institut fur Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universitat Munchen, 81 Editor  
  Language Summary Language Original Title  
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  ISSN ISBN Medium  
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  Notes Approved no  
  Call Number MRC @ kga @ Lahl2007 Serial 596  
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Author Sun, C.M.; Hall, J.A.; Blank, R.B.; Bouladoux, N.; Oukka, M.; Mora, J.R.; Belkaid, Y. url  openurl
  Title Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid Type Journal Article
  Year 2007 Publication J Exp Med Abbreviated Journal  
  Volume Issue (up) Pages  
  Keywords  
  Abstract To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3(+) T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4(+) T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ-derived DCs. This enhanced conversion by LpDCs was dependent on TGF-beta and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion.  
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  Corporate Author Thesis  
  Publisher Place of Publication Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute for Allergy and Infect Editor  
  Language Summary Language Original Title  
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  Notes Approved no  
  Call Number MRC @ kga @ Sun2007 Serial 612  
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Author Moutsatsou, P.; Sekeris, C.E. url  openurl
  Title Steroid receptors in the uterus: implications in endometriosis Type Journal Article
  Year 2003 Publication Ann N Y Acad Sci Abbreviated Journal  
  Volume 997 Issue (up) Pages 209-222  
  Keywords  
  Abstract Receptor proteins for estrogens, progesterone, androgens, and glucocorticoids have been detected in the various cell types of the uterus. Reference is made to the genes encoding these receptors, to the structure of the receptor proteins, and their functional domains. The mode of action of steroid hormones by gene activation, through their cognate receptors, and by nongenomic effects is briefly presented. The role of the steroid receptors in uterine physiology and the significance of the use of steroid receptor knock-out animals in delineating the in vivo action of the hormones is discussed. Recent results on the possible correlation of steroid receptor gene polymorphisms and of quantitative and qualitative changes in the receptor proteins to the etiopathology of endometriosis are reviewed.  
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  Publisher Place of Publication Department of Biological Chemistry, Faculty of Medicine, University of Athens, Athens, Greece. Editor  
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  Area Expedition Conference  
  Notes Approved no  
  Call Number MRC @ kga @ Moutsatsou2003 Serial 619  
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Author Ogle, J.M.; Ramakrishnan, V. url  openurl
  Title Structural insights into translational fidelity Type Journal Article
  Year 2005 Publication Annu Rev Biochem Abbreviated Journal  
  Volume 74 Issue (up) Pages 129-177  
  Keywords  
  Abstract The underlying basis for the accuracy of protein synthesis has been the subject of over four decades of investigation. Recent biochemical and structural data make it possible to understand at least in outline the structural basis for tRNA selection, in which codon recognition by cognate tRNA results in the hydrolysis of GTP by EF-Tu over 75 A away. The ribosome recognizes the geometry of codon-anticodon base pairing at the first two positions but monitors the third, or wobble position, less stringently. Part of the additional binding energy of cognate tRNA is used to induce conformational changes in the ribosome that stabilize a transition state for GTP hydrolysis by EF-Tu and subsequently result in accelerated accommodation of tRNA into the peptidyl transferase center. The transition state for GTP hydrolysis is characterized, among other things, by a distorted tRNA. This picture explains a large body of data on the effect of antibiotics and mutations on translational fidelity. However, many fundamental questions remain, such as the mechanism of activation of GTP hydrolysis by EF-Tu, and the relationship between decoding and frameshifting.  
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  Publisher Place of Publication Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom. james.o Editor  
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  Notes Approved no  
  Call Number MRC @ kga @ Ogle2005 Serial 624  
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Author Beyersdorf, N.; Hanke, T.; Kerkau, T.; Hunig, T. url  openurl
  Title Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases Type Journal Article
  Year 2005 Publication Ann Rheum Dis Abbreviated Journal  
  Volume 64 Suppl 4 Issue (up) Pages iv91-5  
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  Abstract This paper reviews the existing evidence regarding the use of superagonistic anti-CD28 antibodies (CD28 superagonists) for therapeutic manipulation of regulatory T cells (T(reg) cells). The molecular properties of superagonistic anti-CD28 antibodies allow the generation of a strong activating signal in mature T cells, including T(reg) cells, without additional stimulation of the T cell receptor complex. CD28 superagonist administration in vivo leads to the preferential expansion and strong activation of naturally occurring CD4+CD25+CTLA-4+FoxP3+ T(reg) cells over conventional T cells. In animal models, both prophylactic and therapeutic administration of a CD28 superagonist prevented or at least greatly mitigated clinical symptoms and induced remission. Adoptive transfer experiments have further shown that CD28 superagonists mediate protection by expansion and activation of CD4+CD25+ T(reg) cells. Therefore, superagonistic anti-CD28 antibodies offer a promising novel treatment option for human autoimmune diseases and the first clinical trials are eagerly awaited.  
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  Publisher Place of Publication Institute for Virology and Immunobiology, University of Wurzburg, Versbacherstr. 7, 97078 Wurzburg, Editor  
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  Notes Approved no  
  Call Number MRC @ kga @ Beyersdorf2005 Serial 630  
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Author Schwartz, R.H. url  openurl
  Title T cell anergy Type Journal Article
  Year 2003 Publication Annu Rev Immunol Abbreviated Journal  
  Volume 21 Issue (up) Pages 305-334  
  Keywords  
  Abstract T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4(+) and CD8(+) cells fall into two broad categories. One, clonal anergy, is principally a growth arrest state, whereas the other, adaptive tolerance or in vivo anergy, represents a more generalized inhibition of proliferation and effector functions. The former arises from incomplete T cell activation, is mostly observed in previously activated T cells, is maintained by a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40 signaling, and usually does not result in the inhibition of effector functions. The latter is most often initiated in naive T cells in vivo by stimulation in an environment deficient in costimulation or high in coinhibition. Adaptive tolerance can be induced in the thymus or in the periphery. The cells proliferate and differentiate to varying degrees and then downregulate both functions in the face of persistent antigen. The state involves an early block in tyrosine kinase activation, which predominantly inhibits calcium mobilization, and an independent mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance reverses in the absence of antigen. Aspects of both of the anergic states are found in regulatory T cells, possibly preventing them from dominating initial immune responses to foreign antigens and shutting down such responses prematurely.  
  Address  
  Corporate Author Thesis  
  Publisher Place of Publication Laboratory of Cellular and Molecular Immunology, National Institutes of Health, Bethesda, Maryland 2 Editor  
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  Notes Approved no  
  Call Number MRC @ kga @ Schwartz2003 Serial 639  
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Author Lohr, J.; Knoechel, B.; Nagabhushanam, V.; Abbas, A.K. url  openurl
  Title T-cell tolerance and autoimmunity to systemic and tissue-restricted self-antigens Type Journal Article
  Year 2005 Publication Immunol Rev Abbreviated Journal  
  Volume 204 Issue (up) Pages 116-127  
  Keywords Animals; Antigens, Differentiation/genetics/immunology/metabolism; Autoantigens/genetics/*immunology/metabolism; Autoimmunity/genetics/*immunology; Humans; Immune Tolerance/genetics/*immunology; Organ Specificity; T-Lymphocytes/*immunology/metabolism  
  Abstract We have used transgenic mouse models to examine the mechanisms of tolerance in CD4(+) T lymphocytes to soluble, systemic and cell-associated, tissue-restricted self-antigens. Anergy to an islet antigen, as a model of a tissue antigen, is dependent on the inhibitory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4), and tissue-restricted autoimmunity is inhibited by regulatory T lymphocytes. Anergy to a circulating systemic antigen can occur independently of CTLA-4 signals, and it is induced primarily by a block in proximal receptor-initiated signals. CD4(+)CD25(+) regulatory T cells are generated in response to both forms of self-antigens, but the induction is much more efficient with the tissue antigen. Receptor desensitization can be induced by the systemic antigen even in the absence of regulatory T cells, but tolerance can be broken by immunization much more easily if these cells are absent. Deletion of mature T cells is striking with the systemic antigen; there is little evidence to support peripheral deletion as a mechanism of tolerance to the tissue antigen. Thus, both distinct and overlapping mechanisms account for unresponsiveness to different forms of self-antigens. These results establish a foundation for searching for genetic influences and pathogenic mechanisms in organ-specific and systemic autoimmune diseases.  
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  Corporate Author Thesis  
  Publisher Place of Publication Department of Pathology, University of California San Francisco School of Medicine, San Francisco, C Editor  
  Language Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
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  ISSN ISBN Medium  
  Area Expedition Conference  
  Notes 0105-2896Journal ArticleReviewReview, Tutorial Approved no  
  Call Number MRC @ kga @ Lohr2005 Serial 652  
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Author Sundberg, E.J.; Deng, L.; Mariuzza, R.A. url  openurl
  Title TCR recognition of peptide/MHC class II complexes and superantigens Type Journal Article
  Year 2007 Publication Semin Immunol Abbreviated Journal  
  Volume Issue (up) Pages  
  Keywords  
  Abstract Major histocompatibility complex (MHC) class II molecules display peptides to the T cell receptor (TCR). The ability of the TCR to discriminate foreign from self-peptides presented by MHC molecules is a requirement of an effective adaptive immune response. Dysregulation of this molecular recognition event often leads to a disease state. Recently, a number of structural studies have provided significant insight into several such dysregulated interactions between peptide/MHC complexes and TCR molecules. These include TCR recognition of self-peptides, which results in autoimmune reactions, and of mutant self-peptides, common in the immunosurveillance of tumors, as well as the engagement of TCRs by superantigens, a family of bacterial toxins responsible for toxic shock syndrome.  
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  Publisher Place of Publication Boston Biomedical Research Institute, Watertown, MA 02472, USA. Editor  
  Language Summary Language Original Title  
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  Notes Approved no  
  Call Number MRC @ kga @ Sundberg2007 Serial 657  
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Author Greenwald, R.J.; Freeman, G.J.; Sharpe, A.H. url  openurl
  Title The B7 family revisited Type Journal Article
  Year 2005 Publication Annu Rev Immunol Abbreviated Journal  
  Volume 23 Issue (up) Pages 515-548  
  Keywords  
  Abstract The discovery of new functions for the original B7 family members, together with the identification of additional B7 and CD28 family members, have revealed new ways in which the B7:CD28 family regulates T cell activation and tolerance. B7-1/B7-2:CD28 interactions not only promote initial T cell activation but also regulate self-tolerance by supporting CD4+CD25+ T regulatory cell homeostasis. CTLA-4 can exert its inhibitory effects in both B7-1/B7-2 dependent and independent fashions. B7-1 and B7-2 can signal bidirectionally by engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells. The five new B7 family members, ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1) are expressed on professional antigen-presenting cells as well as on cells within nonlymphoid organs, providing new means for regulating T cell activation and tolerance in peripheral tissues. The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and they have important roles in regulating previously activated T cells. PD-1 and BTLA also are expressed on B cells and may have broader immunoregulatory functions. The ICOS:ICOSL pathway appears to be particularly important for stimulating effector T cell responses and T cell-dependent B cell responses, but it also has an important role in regulating T cell tolerance. In addition, the PD-1:PD-L1/PD-L2 pathway plays a critical role in regulating T cell activation and tolerance. In this review, we revisit the roles of the B7:CD28 family members in regulating immune responses, and we discuss their therapeutic potential.  
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  Corporate Author Thesis  
  Publisher Place of Publication Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachuse Editor  
  Language Summary Language Original Title  
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  ISSN ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number MRC @ kga @ Greenwald2005 Serial 665  
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