Defective Induction of CTLA-4 in the NOD Mouse Is Controlled by the NOD Allele of Idd3/IL-2 and a Novel Locus (Ctex) Telomeric on Chromosome 1
Defective Induction of CTLA-4 in the NOD Mouse Is Controlled by the NOD Allele of Idd3/IL-2 and a Novel Locus ( Ctex ) Telomeric on Chromosome 1 Marie Lundholm , Vinicius Motta , Anna Löfgren-Burström , Nadia Duarte , Marie-Louise Bergman , Sofia Mayans and Dan Holmberg From the Department of Medica...
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Published in | Diabetes (New York, N.Y.) Vol. 55; no. 2; pp. 538 - 544 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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Alexandria, VA
American Diabetes Association
01.02.2006
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Abstract | Defective Induction of CTLA-4 in the NOD Mouse Is Controlled by the NOD Allele of Idd3/IL-2 and a Novel Locus ( Ctex ) Telomeric on Chromosome 1
Marie Lundholm ,
Vinicius Motta ,
Anna Löfgren-Burström ,
Nadia Duarte ,
Marie-Louise Bergman ,
Sofia Mayans and
Dan Holmberg
From the Department of Medical Biosciences, Division of Clinical and Medical Genetics, Umeå University, Umeå, Sweden
Address correspondence and reprint requests to Dr. Dan Holmberg, Department of Medical Biosciences, Division of Medical and
Clinical Genetics, Umeå University, S-901 85 Umeå, Sweden. E-mail: dan.holmberg{at}medbio.umu.se
Abstract
Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been
shown to be associated with autoimmune diseases. Previous work has demonstrated a defect in the expression of this molecule
in nonobese diabetic (NOD) mice upon anti-CD3 stimulation in vitro. Using a genetic approach we here demonstrate that a novel
locus (Ctex) telomeric on chromosome 1 together with the Idd3 ( Il-2 ) gene confers optimal CTLA-4 expression upon CD3 activation of T-cells. Based on these data, we provide a model for how gene
interaction between Idd3 ( IL-2 ), Ctex , and Idd5.1 ( Ctla-4 ) could confer susceptibility to autoimmune diabetes in the NOD mouse. Additionally, we showed that the Ctex and the Idd3 regions do not influence inducible T-cell costimulator (ICOS) protein expression in NOD mice. Instead, as previously shown,
higher ICOS levels in NOD mice appear to be controlled by gene(s) in the Idd5.1 region, possibly a polymorphism in the Icos gene itself.
APC, allophycocyanin
CTLA-4, cytotoxic T-lymphocyte–associated antigen 4
FITC, fluorescein isothiocyanate
ICOS, inducible T-cell costimulator
IL, interleukin
LOD, logarithm of odds
mAb, monoclonal antibody
PE, phycoerythrin
TCR, T-cell receptor
QTL, quantitative trait locus
Footnotes
M.L. and V.M. contributed equally to this work.
Accepted November 9, 2005.
Received September 22, 2005.
DIABETES |
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AbstractList | Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been shown to be associated with autoimmune diseases. Previous work has demonstrated a defect in the expression of this molecule in nonobese diabetic (NOD) mice upon anti-CD3 stimulation in vitro. Using a genetic approach we here demonstrate that a novel locus (Ctex) telomeric on chromosome 1 together with the Idd3 (Il-2) gene confers optimal CTLA-4 expression upon CD3 activation of T-cells. Based on these data, we provide a model for how gene interaction between Idd3 (IL-2), Ctex, and Idd5.1 (Ctla-4) could confer susceptibility to autoimmune diabetes in the NOD mouse. Additionally, we showed that the Ctex and the Idd3 regions do not influence inducible T-cell costimulator (ICOS) protein expression in NOD mice. Instead, as previously shown, higher ICOS levels in NOD mice appear to be controlled by gene(s) in the Idd5.1 region, possibly a polymorphism in the Icos gene itself. Defective Induction of CTLA-4 in the NOD Mouse Is Controlled by the NOD Allele of Idd3/IL-2 and a Novel Locus ( Ctex ) Telomeric on Chromosome 1 Marie Lundholm , Vinicius Motta , Anna Löfgren-Burström , Nadia Duarte , Marie-Louise Bergman , Sofia Mayans and Dan Holmberg From the Department of Medical Biosciences, Division of Clinical and Medical Genetics, Umeå University, Umeå, Sweden Address correspondence and reprint requests to Dr. Dan Holmberg, Department of Medical Biosciences, Division of Medical and Clinical Genetics, Umeå University, S-901 85 Umeå, Sweden. E-mail: dan.holmberg{at}medbio.umu.se Abstract Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been shown to be associated with autoimmune diseases. Previous work has demonstrated a defect in the expression of this molecule in nonobese diabetic (NOD) mice upon anti-CD3 stimulation in vitro. Using a genetic approach we here demonstrate that a novel locus (Ctex) telomeric on chromosome 1 together with the Idd3 ( Il-2 ) gene confers optimal CTLA-4 expression upon CD3 activation of T-cells. Based on these data, we provide a model for how gene interaction between Idd3 ( IL-2 ), Ctex , and Idd5.1 ( Ctla-4 ) could confer susceptibility to autoimmune diabetes in the NOD mouse. Additionally, we showed that the Ctex and the Idd3 regions do not influence inducible T-cell costimulator (ICOS) protein expression in NOD mice. Instead, as previously shown, higher ICOS levels in NOD mice appear to be controlled by gene(s) in the Idd5.1 region, possibly a polymorphism in the Icos gene itself. APC, allophycocyanin CTLA-4, cytotoxic T-lymphocyte–associated antigen 4 FITC, fluorescein isothiocyanate ICOS, inducible T-cell costimulator IL, interleukin LOD, logarithm of odds mAb, monoclonal antibody PE, phycoerythrin TCR, T-cell receptor QTL, quantitative trait locus Footnotes M.L. and V.M. contributed equally to this work. Accepted November 9, 2005. Received September 22, 2005. DIABETES |
Audience | Professional |
Author | Nadia Duarte Marie Lundholm Dan Holmberg Sofia Mayans Vinicius Motta Anna Löfgren-Burström Marie-Louise Bergman |
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Keywords | Endocrinopathy Vertebrata Allele Mammalia Interleukin 2 Mouse Animal Diabetes mellitus Cytokine Rodentia Chromosome Locus Mammalian/genetics Antigens CD Differentiation/genetics/metabolism Cultured Mice Inbred NOD Chromosomes Cells Inbred C57BL |
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Snippet | Defective Induction of CTLA-4 in the NOD Mouse Is Controlled by the NOD Allele of Idd3/IL-2 and a Novel Locus ( Ctex ) Telomeric on Chromosome 1
Marie Lundholm... Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been shown to be associated with... Cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been shown to be associated with... Cytotoxic T-lymphocyte--associated antigen-4 (CTLA-4), or CD152, is a negative regulator of T-cell activation and has been shown to be associated with... |
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SubjectTerms | Alleles Animals Antigens Antigens, CD Antigens, Differentiation - genetics Antigens, Differentiation - metabolism Autoimmune diseases Biological and medical sciences Cells Cells, Cultured Chromosomes Chromosomes, Mammalian - genetics Cloning CTLA-4 Antigen Cytotoxicity Diabetes Diabetes mellitus Diabetes Mellitus - genetics Diabetes research Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Female Flow cytometry Gene Expression Regulation Genetic aspects Genetic Predisposition to Disease Genotype Interleukin-2 - genetics Ligands Lymphocytes Medical sciences Mice Mice, Inbred C57BL Mice, Inbred NOD Pancreatic beta cells Physical Chromosome Mapping Spleen - cytology T cells Telomere - genetics |
Title | Defective Induction of CTLA-4 in the NOD Mouse Is Controlled by the NOD Allele of Idd3/IL-2 and a Novel Locus (Ctex) Telomeric on Chromosome 1 |
URI | http://diabetes.diabetesjournals.org/content/55/2/538.abstract https://www.ncbi.nlm.nih.gov/pubmed/16443792 https://www.proquest.com/docview/216483029/abstract/ https://search.proquest.com/docview/17477360 https://search.proquest.com/docview/70715460 https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-15296 |
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