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.
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.
Lundholm
Marie
M
Department of Medical Biosciences, Division of Medical and Clinical Genetics, Umeå University, Sweden.
Motta
Vinicius
V
Löfgren-Burström
Anna
A
Duarte
Nadia
N
Bergman
Marie-Louise
ML
Mayans
Sofia
S
Holmberg
Dan
D
D000483:Alleles; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D007376:Interleukin-2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D020161:Physical Chromosome Mapping; D013154:Spleen / Q000166:cytology; D016615:Telomere / Q000235:genetics*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007376:Interleukin-2