Variation in the Cd3 zeta (Cd247) gene correlates with altered T cell activation and is associated with autoimmune diabetes.
Tuning of TCR-mediated activation was demonstrated to be critical for lineage fate in T cell development, as well as in the control of autoimmunity. In this study, we identify a novel diabetes susceptibility gene, Idd28, in the NOD mouse and provide evidence that Cd3zeta (Cd247) constitutes a prime candidate gene for this locus. Moreover, we show that the allele of the Cd3zeta gene expressed in NOD and DBA/2 mouse strains confers lower levels of T cell activation compared with the allele expressed by C57BL/6 (B6), BALB/c, and C3H/HeJ mice. These results support a model in which the development of autoimmune diabetes is dependent on a TCR signal mediated by a less-efficient NOD allele of the Cd3zeta gene.
Lundholm
Marie
M
Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
Mayans
Sofia
S
Motta
Vinicius
V
Löfgren-Burström
Anna
A
Danska
Jayne
J
Holmberg
Dan
D
D000483:Alleles; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017252:CD3 Complex / Q000235:genetics* / Q000502:physiology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000172:deficiency; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000276:immunology*; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D006131:Growth Inhibitors