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*Center for Neurologic Diseases and
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom;
Department of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065; and
¶Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 L.S.W. is supported by grants from the Juvenile Diabetes Research Foundation, the Wellcome Trust, and the National Institutes of Health (P01 AI39671). L.S.W. is a JDRF/WT Principal Research Fellow. V.K.K. is supported by grants from the National Institutes of Health (R01 AI044880, P01 AI 56299, P01 AI 39671, and NS046414) and the Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard. M.A. is supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (079895). The availability of NOD-congenic mice through the Taconic Farms Emerging Models Program has been supported by grants from the Merck Genome Research Institute, National Institute of Allergy and Infectious Disease, and the Juvenile Diabetes Research Foundation.
2 M.A. and D.C. contributed equally to this work.
3 V.K.K. and L.S.W. contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Vijay K. Kuchroo, Center for Neurologic Diseases, 77 Avenue Louis Pasteur HIM 780, Boston, MA 02115 and Dr. Linda S. Wicker, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY U.K. E-mail addresses: vkuchroo{at}rics.bwh.harvard.edu and linda.wicker{at}cimr.cam.ac.uk
5 Abbreviations used in this paper: T1D, type 1 diabetes; Idd, insulin-dependent diabetes; flCTLA-4, full-length CTLA-4; liCTLA-4, ligand-independent CTLA-4; tg, transgenic; WT, wild type; MFI, mean fluorescence intensity; SHP-2, Src homology region 2 domain-containing phosphatase 1; Ct, threshold cycle; SNP, single-nucleotide polymorphism; ACADL, long-chain acyl-coenzyme A dehydrogenase.
6 The online version of this article contains supplemental material.
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