title: The B7-independent isoform of CTLA-4 functions to regulate autoimmune diabetes.
abstract: The critical role of CTLA-4 in inhibiting Ag-driven T cell responses upon engagement with its ligands, B7-1 and B7-2 and its importance for peripheral T cell tolerance and T cell homeostasis has been studied intensively. The CTLA-4 splice variant ligand-independent (li)-CTLA-4 is expressed in naive and activated T cells and can actively alter T cell signaling despite its lack of a B7 binding domain. To study the effect of li-CTLA-4 in regulating T cell responses in the context of autoimmunity, we engineered a B6.CTLA-4 (floxed-Exon2)-BAC-transgene, resulting in selective expression of li-CTLA-4 upon Cre-mediated deletion of Exon 2. Introducing the B6.BAC into the NOD background, which is genetically deficient for li-CTLA-4, restores mRNA levels of li-CTLA-4 to those observed in C57BL/6 mice. Furthermore, re-expressing this ligand nonbinding isoform in NOD mice reduced IFN-γ production in T effector cells accompanied by a significant decrease in insulitis and type 1 diabetes frequency. However, selective expression of li-CTLA-4 could not fully rescue the CTLA-4 knockout disease phenotype when bred onto NOD.BDC2.5.CTLA-4 knockout background because of the requirement of the full-length, B7-binding CTLA-4 molecule on T effector cells. Thus, the li-CTLA-4 form, when expressed at physiologic levels in the CTLA-4-sufficient NOD background can suppress autoimmunity; however, the functionality of the li-CTLA-4 isoform depends on the presence of the full-length molecule to alter effector T cell signaling.
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Stumpf
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zhou
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D060908:CTLA-4 Antigen / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D007108:Immune Tolerance / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D011236:Prediabetic State / Q000276:immunology / Q000473:pathology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation
chemical_list: D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger