Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood
- 25 April 2016
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 113 (17), E2383-E2392
- https://doi.org/10.1073/pnas.1603892113
Abstract
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is essential for immunological (self-) tolerance, but due to the early fatality of CTLA-4 KO mice, its specific function in central and peripheral tolerance and in different systemic diseases remains to be determined. Here, we further examined the role of CTLA-4 by abrogating CTLA-4 expression in adult mice and compared the resulting autoimmunity that follows with that produced by congenital CTLA-4 deficiency. We found that conditional deletion of CTLA-4 in adult mice resulted in spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, accompanied by organ-specific autoantibodies. However, in contrast to congenital deficiency, this was not fatal. CTLA-4 deletion induced preferential expansion of CD4(+) Foxp3(+) Treg cells. However, T cells from CTLA-4-deficient inducible KO mice were able to adoptively transfer the diseases into T cell-deficient mice. Notably, cell transfer of thymocytes de novo produced myocarditis, otherwise not observed in donor mice depleted in adulthood. Moreover, CTLA-4 deletion in adult mice had opposing impacts on induced autoimmune models. Thus, although CTLA-4-deficient mice had more severe collagen-induced arthritis (CIA), they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE); however, onset of protein-induced EAE was only delayed. Collectively, this indicates that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cell-mediated suppression.Funding Information
- Vetenskapsrådet (522-2009- 2548)
- Åke Wibergs Stiftelse (367990049; 924563126; 940219686)
- Knut och Alice Wallenbergs Stiftelse (KAW 2010.0148)
- Ministry of Education, Culture, Sports, Science, and Technology (26253030)
- Core Research for Evolutional Science and Technology, Japan Science and Technology Agency (15652235)
- Vetenskapsrådet (521-2010-2894)
This publication has 63 references indexed in Scilit:
- CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoireProceedings of the National Academy of Sciences of the United States of America, 2013
- Manifestation of Spontaneous and Early Autoimmune Gastritis in CCR7-Deficient MiceThe American Journal of Pathology, 2011
- Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4Science, 2011
- RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammationNature Immunology, 2011
- High prevalence of low affinity peptide–MHC II tetramer–negative effectors during polyclonal CD4+ T cell responsesThe Journal of Experimental Medicine, 2011
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaNew England Journal of Medicine, 2010
- CTLA-4 suppresses the pathogenicity of self antigen–specific T cells by cell-intrinsic and cell-extrinsic mechanismsNature Immunology, 2009
- Enhanced selection of FoxP3 + T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune diseaseProceedings of the National Academy of Sciences of the United States of America, 2009
- Foxp3+natural regulatory T cells preferentially form aggregates on dendritic cellsin vitroand actively inhibit their maturationProceedings of the National Academy of Sciences of the United States of America, 2008
- Use of Dinitrosalicylic Acid Reagent for Determination of Reducing SugarAnalytical Chemistry, 1959