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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

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

Key Words: 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

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.

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