CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice.
The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.
Department of Cell and Molecular Biology, University of Umeå, S-901 87 Umeå Sweden.
M L
ML
Bergman
C M
CM
Cilio
C
C
Penha-Gonçalves
S E
SE
Lamhamedi-Cherradi
A
A
Löfgren
F
F
Colucci
K
K
Lejon
H J
HJ
Garchon
D
D
Holmberg
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D015551:Autoimmunity; D060908:CTLA-4 Antigen; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005720:Gamma Rays; D018796:Immunoconjugates; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011836:Radiation Tolerance; D013601:T-Lymphocytes / Q000166:cytology / Q000528:radiation effects*; D013950:Thymus Gland / Q000166:cytology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept