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Author Blattman, J.N.; Greenberg, P.D. url  openurl
  Title Cancer immunotherapy: a treatment for the masses Type Journal Article
  Year 2004 Publication Science Abbreviated Journal  
  Volume 305 Issue 5681 Pages 200-205  
  Keywords (up)  
  Abstract Cancer immunotherapy attempts to harness the exquisite power and specificity of the immune system for the treatment of malignancy. Although cancer cells are less immunogenic than pathogens, the immune system is clearly capable of recognizing and eliminating tumor cells. However, tumors frequently interfere with the development and function of immune responses. Thus, the challenge for immunotherapy is to use advances in cellular and molecular immunology to develop strategies that effectively and safely augment antitumor responses.  
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  Publisher Place of Publication Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA. Editor  
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  Call Number MRC @ kga @ Blattman2004 Serial 110  
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Author Sachs, K.; Perez, O.; Pe'er, D.; Lauffenburger, D.A.; Nolan, G.P. url  openurl
  Title Causal protein-signaling networks derived from multiparameter single-cell data Type Journal Article
  Year 2005 Publication Science Abbreviated Journal  
  Volume 308 Issue 5721 Pages 523-529  
  Keywords (up)  
  Abstract Machine learning was applied for the automated derivation of causal influences in cellular signaling networks. This derivation relied on the simultaneous measurement of multiple phosphorylated protein and phospholipid components in thousands of individual primary human immune system cells. Perturbing these cells with molecular interventions drove the ordering of connections between pathway components, wherein Bayesian network computational methods automatically elucidated most of the traditionally reported signaling relationships and predicted novel interpathway network causalities, which we verified experimentally. Reconstruction of network models from physiologically relevant primary single cells might be applied to understanding native-state tissue signaling biology, complex drug actions, and dysfunctional signaling in diseased cells.  
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  Publisher Place of Publication Biological Engineering Division, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, U Editor  
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  Notes Approved no  
  Call Number MRC @ kga @ Sachs2005 Serial 111  
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Author Yurchenko, E.; Tritt, M.; Hay, V.; Shevach, E.M.; Belkaid, Y.; Piccirillo, C.A. url  openurl
  Title CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence Type Journal Article
  Year 2006 Publication J Exp Med Abbreviated Journal  
  Volume 203 Issue 11 Pages 2451-2460  
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  Abstract Pathogen persistence after clinical cure is a hallmark of many chronic infections. Previously, we showed that naturally occurring CD4+CD25+ regulatory T (nTreg) cells rapidly accumulate within chronic dermal sites of Leishmania major infection where they suppress anti-pathogen CD4+ T cell responses, favor parasite persistence and dermal pathology, and consequently control concomitant immunity. Here, we postulated that chemokines might direct nTreg cell homing in sites of infection and show that CD4+CD25+ nTreg cells, compared with normal CD4+ T cells, preferentially express the CCR5 chemokine receptor, which enables them to migrate in response to CCR5 ligands in vitro. We show that in contrast to their wild-type (WT) counterparts, CCR5-/- CD4+CD25+ nTreg cells resulted in an increased magnitude of parasite-specific, interferon gamma-producing CD4+ T cells within infection sites, dramatically reduced parasite numbers, and potent resistance to infection, a finding consistent with the clinical outcome of infected CCR5-/- mice. Interestingly, this resistance was related to an inefficient migration of CCR5-/- nTreg cells to infected dermal sites compared with WT nTreg cells. Thus, this study shows that CCR5 directs the homing of CD4+CD25+ nTreg cells to L. major-infected dermal sites where they promote the establishment of infection and long-term survival of the parasite in the immune host.  
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  Publisher Place of Publication Department of Microbiology and Immunology, McGill University, Montreal, H3A 2B4, Canada. Editor  
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  Call Number MRC @ kga @ Yurchenko2006 Serial 112  
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Author Schneider, M.A.; Meingassner, J.G.; Lipp, M.; Moore, H.D.; Rot, A. url  openurl
  Title CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells Type Journal Article
  Year 2007 Publication J Exp Med Abbreviated Journal  
  Volume 204 Issue 4 Pages 735-745  
  Keywords (up)  
  Abstract CCR7-mediated migration of naive T cells into the secondary lymphoid organs is a prerequisite for their encounter with mature dendritic cells, the productive presentation of cognate antigen, and consequent T cell proliferation and effector differentiation. Therefore, CCR7 was suggested to play an important role in the initiation of adaptive immune responses. In this study, we show that primary immunity can also develop in the absence of CCR7. Moreover, CCR7-deficient knockout (KO) mice display augmented immune responses. Our data cumulatively suggest that enhanced immunity in CCR7 KO mice is caused by the defective lymph node (LN) positioning of FoxP3(+) CD4(+) CD25(+) regulatory T cells (T reg cells) and the consequent impediment of their function. The FoxP3(+) T reg cells express CCR7 and, after their adoptive transfer, migrate into the LNs of wild-type mice. Here, they proliferate in situ upon antigen stimulation and inhibit the generation of antigen-specific T cells. Conversely, transferred CCR7-deficient T reg cells fail to migrate into the LNs and suppress antigen-induced T cell responses. The transfer of combinations of naive and T reg cells from wild-type and CCR7 KO mice into syngeneic severe combined immunodeficient mice directly demonstrates that CCR7-deficient T reg cells are less effective than their wild-type counterparts in preventing the development of inflammatory bowel disease.  
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  Publisher Place of Publication Novartis Institutes for BioMedical Research, A1235 Vienna, Austria. Editor  
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  Notes Approved no  
  Call Number MRC @ kga @ Schneider2007 Serial 113  
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Author Marski, M.; Kandula, S.; Turner, J.R.; Abraham, C. url  openurl
  Title CD18 is required for optimal development and function of CD4+CD25+ T regulatory cells Type Journal Article
  Year 2005 Publication J Immunol Abbreviated Journal  
  Volume 175 Issue 12 Pages 7889-7897  
  Keywords (up)  
  Abstract CD4+CD25+ T regulatory (Treg) cells inhibit immunopathology and autoimmune disease in vivo. CD4+CD25+ Treg cells' capacity to inhibit conventional T cells in vitro is dependent upon cell-cell contact; however, the cell surface molecules mediating this cell:cell contact have not yet been identified. LFA-1 (CD11a/CD18) is an adhesion molecule that plays an established role in T cell-mediated cell contact and in T cell activation. Although expressed at high levels on murine CD4+CD25+ Treg cells, the role of LFA-1 in these cells has not been defined previously. We hypothesized that LFA-1 may play a role in murine CD4+CD25+ Treg function. To evaluate this, we analyzed LFA-1-deficient (CD18-/-) CD4+CD25+ T cells. We show that CD18-/- mice demonstrate a propensity to autoimmunity. Absence of CD18 led to diminished CD4+CD25+ T cell numbers and affected both thymic and peripheral development of these cells. LFA-1-deficient CD4+CD25+ T cells were deficient in mediating suppression in vitro and in mediating protection from colitis induced by the transfer of CD4+CD25- T cells into lymphopenic hosts. Therefore, we define a crucial role for CD18 in optimal CD4+CD25+ Treg development and function.  
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  Publisher Place of Publication Department of Medicine, University of Chicago, IL 60637, USA. Editor  
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  Call Number MRC @ kga @ Marski2005 Serial 114  
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Author Tarbell, K.V.; Yamazaki, S.; Olson, K.; Toy, P.; Steinman, R.M. url  openurl
  Title CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes Type Journal Article
  Year 2004 Publication J Exp Med Abbreviated Journal  
  Volume 199 Issue 11 Pages 1467-1477  
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  Abstract In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet beta cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 10(5) polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.  
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  Publisher Place of Publication Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New Editor  
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  Call Number MRC @ kga @ Tarbell2004 Serial 116  
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Author Venturi, G.M.; Conway, R.M.; Steeber, D.A.; Tedder, T.F. url  openurl
  Title CD25+CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover Type Journal Article
  Year 2007 Publication J Immunol Abbreviated Journal  
  Volume 178 Issue 1 Pages 291-300  
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  Abstract The molecular mechanisms controlling regulatory CD25(+)Foxp3(+)CD4(+) T cell (T(reg)) migration are central to in vivo immune responses. T(reg) cell subsets differentially express L-selectin, an adhesion molecule mediating lymphocyte migration to peripheral LNs (PLNs) and leukocyte rolling during inflammation. In this study, L-selectin was essential for T(reg) cell migration and normal tissue distribution. Specifically, there was a 90% reduction in PLN T(reg) cells in L-selectin(-/-) mice with a compensatory increase in spleen T(reg) cell numbers. Unexpectedly, however, 40% of the CD4(+) T cells remaining within PLNs of L-selectin(-/-) mice were T(reg) cells. The migratory properties of T(reg) cells were nonetheless markedly different from those of naive CD4(+) T cells, with 3- to 9-fold lower migration of T(reg) cells into PLNs and approximately 2-fold lower migration into the spleen. T(reg) cells also turned over cell surface L-selectin at a faster rate than CD25(-)CD4(+) T cells, but maintained physiologically appropriate L-selectin densities for optimal migration. Specifically, T(reg) cells expressed 30-40% more cell surface L-selectin when its endoproteolytic cleavage was blocked genetically, which resulted in a 2-fold increase in T(reg) cell migration into PLNs. However, increased L-selectin cleavage by T(reg) cells in wild-type mice was accompanied by 2-fold higher L-selectin mRNA levels, which resulted in equivalent cell surface L-selectin densities on T(reg) and naive T cells. Thus, T(reg) cells and CD25(-)CD4(+) T cells share similar requirements for L-selectin expression during migration, although additional molecular mechanisms constrain T(reg) cell migration beyond what is required for naive CD4(+) T cell migration.  
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  Publisher Place of Publication Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA. Editor  
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  Call Number MRC @ kga @ Venturi2007 Serial 117  
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Author Curotto de Lafaille, M.A.; Lino, A.C.; Kutchukhidze, N.; Lafaille, J.J. url  openurl
  Title CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion Type Journal Article
  Year 2004 Publication J Immunol Abbreviated Journal  
  Volume 173 Issue 12 Pages 7259-7268  
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  Abstract Naturally occurring CD4(+) regulatory T cells are generally identified through their expression of CD25. However, in several experimental systems considerable T(reg) activity has been observed in the CD4(+)CD25(-) fraction. Upon adoptive transfer, the expression of CD25 in donor-derived cells is not stable, with CD4(+)CD25(+) cells appearing in CD4(+)CD25(-) T cell-injected animals and vice versa. We show in this study that CD25(+) cells arising from donor CD25(-) cells upon homeostatic proliferation in recipient mice express markers of freshly isolated T(reg) cells, display an anergic state, and suppress the proliferation of other cells in vitro. The maintenance of CD25 expression by CD4(+)CD25(+) cells depends on IL-2 secreted by cotransferred CD4(+)CD25(-) or by Ag-stimulated T cells in peripheral lymphoid organs.  
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  Publisher Place of Publication Molecular Pathogenesis Program, Skirball Institute, and Department of Pathology, New York University Editor  
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  Call Number MRC @ kga @ CurottodeLafaille2004 Serial 119  
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Author Malek, T.R.; Yu, A.; Vincek, V.; Scibelli, P.; Kong, L. url  openurl
  Title CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2 Type Journal Article
  Year 2002 Publication Immunity Abbreviated Journal  
  Volume 17 Issue 2 Pages 167-178  
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  Abstract Lethal autoimmunity associated with IL-2Rbeta-deficient mice is prevented after thymic transgenic expression of wild-type IL-2Rbeta in IL-2Rbeta(-/-) mice (Tg -/- mice). Here, we show that CD4(+)CD25(+) regulatory T cells were not readily detected in IL-2Rbeta(-/-) mice, but the production of functional CD4(+)CD25(+) T cells was reconstituted in Tg -/- mice. Adoptive transfer of normal CD4(+)CD25(+) T cells into neonatal IL-2Rbeta-deficient mice prevented this lethal autoimmune syndrome. The CD4(+)CD25(+) T cells in disease-free adult IL-2Rbeta-deficient recipient mice were present at a near normal frequency, were solely donor-derived, and depended on IL-2 for expansion. These observations indicate that the essential function of the IL-2/IL-2R system primarily lies at the level of the production of CD4(+)CD25(+) regulatory T cells.  
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  Publisher Place of Publication Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101, USA. tm Editor  
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  Call Number MRC @ kga @ Malek2002 Serial 121  
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Author Caton, A.J.; Cozzo, C.; Larkin, J. 3rd; Lerman, M.A.; Boesteanu, A.; Jordan, M.S. url  openurl
  Title CD4(+) CD25(+) regulatory T cell selection Type Journal Article
  Year 2004 Publication Ann N Y Acad Sci Abbreviated Journal  
  Volume 1029 Issue Pages 101-114  
  Keywords (up)  
  Abstract Accumulating evidence indicates that regulatory T cells play a crucial role in preventing autoimmunity. To examine the processes by which regulatory CD4(+) T cells are produced during immune repertoire formation, we have developed transgenic mice that express the influenza virus hemagglutinin (HA) and coexpress major histocompatibility complex class II-restricted T cell receptors (TCRs) with varying affinities for the HA-derived CD4(+) T cell determinant S1. We show 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 S1 do not undergo selection into this pathway. We show that CD4(+) thymocytes with identical specificity for the S1 self-peptide can undergo overt deletion versus abundant selection to become CD4(+) CD25(+) regulatory T cells in response to variations in expression of the S1 self-peptide in different lineages of HA transgenic mice. We also show that CD4(+) CD25(+) T cells proliferate in response to their selecting self-peptide in the periphery. Moreover, they do not proliferate in response to lymphopenia in the absence of the selecting self-peptide, reflecting a low level of expression of the high-affinity receptor for IL-7 (CD127) relative to conventional CD4(+) T cells. These studies are determining how specificity for self-peptides directs the thymic selection and peripheral expansion of CD4(+) CD25(+) regulatory T cells. Moreover, the differing responsiveness of CD4(+) CD25(+) regulatory T cells to cytokine- versus self-peptide-mediated signals may direct their accumulation to sites where the self-peptide is expressed.  
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  Publisher Place of Publication The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104, USA. caton@wistar.upenn.edu Editor  
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  Notes Approved no  
  Call Number MRC @ kga @ Caton2004 Serial 122  
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