@article {542311,
	title = {Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice.},
	journal = {J Immunol},
	volume = {183},
	number = {8},
	year = {2009},
	month = {2009 Oct 15},
	pages = {5146-57},
	abstract = {Idd5.1 regulates T1D susceptibility in nonobese diabetic (NOD) mice and has two notable candidate genes, Ctla4 and Icos. Reduced expression of one of the four CTLA-4 isoforms, ligand-independent CTLA-4 (liCTLA-4), which inhibits in vitro T cell activation and cytokine production similarly to full-length CTLA-4 (flCTLA-4), has been hypothesized to increase type 1 diabetes (T1D) susceptibility. However, further support of this hypothesis is required since the Idd5.1 haplotypes of the diabetes-susceptible NOD and the resistant B10 strains differ throughout Ctla4 and Icos. Using haplotype analysis and the generation of novel Idd5.1-congenic strains that differ at the disease-associated Ctla4 exon 2 single-nucleotide polymorphism, we demonstrate that increased expression of liCTLA-4 correlates with reduced T1D susceptibility. To directly assess the ability of liCTLA-4 to modulate T1D, we generated liCTLA-4-transgenic NOD mice and compared their diabetes susceptibility to nontransgenic littermates. NOD liCTLA-4-transgenic mice were protected from T1D to the same extent as NOD.B10 Idd5.1-congenic mice, demonstrating that increased liCTLA-4 expression alone can account for disease protection. To further investigate the in vivo function of liCTLA-4, specifically whether liCTLA-4 can functionally replace flCTLA-4 in vivo, we expressed the liCTLA-4 transgene in CTLA-4(-/-) B6 mice. CTLA-4(-/-) mice expressing liCTLA-4 accumulated fewer activated effector/memory CD4(+) T cells than CTLA-4(-/-) mice and the transgenic mice were partially rescued from the multiorgan inflammation and early lethality caused by the disruption of Ctla4. These results suggest that liCTLA-4 can partially replace some functions of flCTLA-4 in vivo and that this isoform evolved to reinforce the function of flCTLA-4.},
	keywords = {Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Autoimmunity, CTLA-4 Antigen, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Haplotypes, Inducible T-Cell Co-Stimulator Protein, Interferon-gamma, Interleukin-17, Lymphocyte Activation, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, Transgenic, Polymorphism, Single Nucleotide, Protein Isoforms, T-Lymphocytes},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.0802610},
	author = {Araki, Manabu and Chung, Denise and Liu, Sue and Rainbow, Daniel B and Chamberlain, Giselle and Garner, Valerie and Hunter, Kara M D and Vijayakrishnan, Lalitha and Peterson, Laurence B and Oukka, Mohamed and Sharpe, Arlene H and Sobel, Raymond and Kuchroo, Vijay K and Wicker, Linda S}
}
