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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
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
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2006 (Engelska)Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, nr 2, s. 538-544Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2006. Vol. 55, nr 2, s. 538-544
Nyckelord [en]
Alleles, Animals, Antigens; CD, Antigens; Differentiation/genetics/*metabolism, Cells; Cultured, Chromosomes; Mammalian/*genetics, Diabetes Mellitus/*genetics, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genotype, Interleukin-2/*genetics, Mice, Mice; Inbred C57BL, Mice; Inbred NOD, Physical Chromosome Mapping, Spleen/cytology, Telomere/*genetics
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-15296DOI: 10.2337/diabetes.55.02.06.db05-1240ISI: 000235178400037PubMedID: 16443792Scopus ID: 2-s2.0-33644753940OAI: oai:DiVA.org:umu-15296DiVA, id: diva2:154968
Tillgänglig från: 2008-01-11 Skapad: 2008-01-11 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. The genetic basis of T and B cell contribution to autoimmune diabetes in NOD mice
Öppna denna publikation i ny flik eller fönster >>The genetic basis of T and B cell contribution to autoimmune diabetes in NOD mice
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The nonobese diabetic mouse (NOD) is an excellent animal model to study type 1 diabetes. As with some humans, disease in the NOD mouse is effected by a combination of genetic and environmental factors. At least 20 insulin dependent diabetes (Idd) susceptibility loci have been identified so far, both in humans and in the NOD mouse.

In this thesis, the overall aim has been to understand the genetic basis of diabetes in the NOD mouse by assessing immunogically-related phenotypes. As lymphocytes are the main players in the onset and progression to overt diabetes, we searched for physiological abnormalities in T and B cells, which could contribute to the breakdown of tolerance to pancreatic antigens. Ultimately, we postulate that abnormalities in the T or B cell compartments, under the genetic control of a previously defined diabetes susceptibility regions (Idds) could unravel the biological mechanisms underlying diabetes susceptibility and facilitate the identification of etiological polymorphisms involved in the disease.

NOD T cells are defective in upregulating CTLA-4 upon in vitro activation. Previous studies have shown that this defect is, at least in part, controlled by gene(s) in the Idd5 region on chromosome 1. In paper I, we provide evidence that defective upregulation of the CTLA-4 in NOD T cells is not controlled by the Idd5.1 and Idd5.2 regions, but rather by genes linked to the telomeric region of chromosome 1 and to the Idd3 locus, for which the prime candidate gene is Il-2. Interestingly, we could restore some of the defective CTLA-4 expression in NOD T cells by the addition of exogenous IL-2 during T cell activation in vitro. In paper II, we show that NOD thymocytes are resistant to superantigen-mediated negative selection and that this trait is under control of the Idd5.2 region. Interestingly, it appears to operate in a T cell non-autonomous manner. In paper III, we describe a competitive advantage of NOD thymocytes to mature when they co-develop with B6 thymocytes in embryo aggregation chimeras. These results imply that defects exist in the positive/negative selection mechanisms in the NOD thymus. Apart from T cells, B cells also play an important role in the initiation of diabetes in NOD mice, probably as antigen presenting cells. In paper IV, we report that the genetic basis of an enlarged marginal zone (MZ) B cell population observed in the NOD mice is linked to the Idd9/Idd11 region. Together, these findings contribute to the dissection of the molecular mechanisms underlying diabetes pathogenesis, and shed light on the contribution of central and peripheral tolerance mechanisms to this process.

Ort, förlag, år, upplaga, sidor
Umeå: Medicinsk biovetenskap, 2006. s. 108
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1015
Nyckelord
Type 1 Diabetes, NOD mouse, CTLA-4, superantigen, T cells, Idd, marginal zone B cells, embryo aggregation chimera, negative selection
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-728 (URN)91-7264-006-5 (ISBN)
Disputation
2006-03-31, Betula, 6M, Norrlands Universitetssjukhuset,, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-03-14 Skapad: 2006-03-14 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
2. Functional studies of candidate genes contributing to type 1 diabetes in the NOD mouse
Öppna denna publikation i ny flik eller fönster >>Functional studies of candidate genes contributing to type 1 diabetes in the NOD mouse
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Type 1 Diabetes (T1D) is an autoimmune disorder caused by both genetic and environmental factors. The non-obese diabetic (NOD) mouse is one of the best and most commonly studied animal models for T1D. This mouse strain spontaneously develops diabetes through a process that closely resembles the human pathogenesis. More than 20 insulin dependent susceptibility (Idd) loci have been identified in the NOD mouse, contributing to disease susceptibility; however, the contribution of each of the various factors to disease pathogenesis is largely unknown.

The aim of this thesis was to identify and functionally characterize candidate genes mediating susceptibility to murine T1D.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T-cell activation and has been shown to be associated with autoimmune diseases. Genetic analyses of the NOD mouse have identified the Ctla-4 gene as a major candidate for the Idd5.1 diabetes susceptibility locus and NOD mice have been found to display an impaired expression of CTLA-4 upon anti-CD3 stimulation in vitro. In Paper I, we showed that a novel locus (Ctex) in the distal part of the chromosome 1 together with the Idd3 (Il-2) locus on chromosome 3, constitute the major factors conferring the observed difference in CTLA-4 expression levels. Moreover, we also demonstrated that the defective expression of CTLA-4 in NOD T-cells can in part be overcome by the addition of exogenous interleukin-2 (IL-2). In Paper II, using congenic mice, we confirmed that the Ctex locus contributes to decreased expression of CTLA-4 observed in NOD mice and restricted the region of interest to a 28.8 Mb region containing the Cd3ζ gene. We also demonstrated a phenotypic correlation between strains carrying the NOD versus C57BL/6 alleles of Cd3ζ, respectively and showed that expression of CD3ζ is impaired in activated NOD CD4+ T cells. The NOD allele of the Cd3ζ region was found to confer impaired T cell activation and the defective CD3 signalling could be surpassed by PMA plus ionomycin stimulation supporting the notion of CD3ζ as a prime candidate gene for Ctex.

NOD lymphocytes display relative resistance to various apoptosis-inducing signals, which have been proposed to contribute to the pathogenesis of diabetes. Resistance to dexamethasone-induced apoptosis in NOD immature thymocytes has been mapped to the Idd6 locus. In Paper III we restricted the Idd6 locus to an 8 cM region on the telomeric end of chromosome 6 using a set of congenic mice. In addition, we could confirm that the Idd6 region controls apoptosis resistance in immature thymocytes and restricted the control of apoptosis resistance to a 3 cM region within the Idd6 locus. In Paper IV, we further restricted the Idd6 locus to a 3 Mb region and excluded the region controlling the resistance to apoptosis as directly mediating susceptibility to diabetes. We also showed that defective expression of the Lrmp/Jaw1 gene, encoding an endoplasmatic reticulum resident protein, is controlled by the Idd6 locus making it the prime candidate for Idd6

Together, these results contribute to the identification and functional characterization of candidate genes that may confer susceptibility to T1D in the NOD mouse. These results offer important insights into the pathophysiological processes underlying this disease.

Ort, förlag, år, upplaga, sidor
Umeå: Medicinsk biovetenskap, 2009. s. 81
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1262
Nyckelord
Type 1 Diabetes, NOD mouse, CTLA-4, Ctex, CD3ζ, apoptosis, Idd6, Lrmp
Forskningsämne
medicinsk genetik
Identifikatorer
urn:nbn:se:umu:diva-22401 (URN)978-91-7264-778-7 (ISBN)
Disputation
2009-09-04, Hörsal Betula, byggnad 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-05-20 Skapad: 2009-05-07 Senast uppdaterad: 2009-05-20Bibliografiskt granskad

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