title: Transgenic expression of CTLA-4 controls lymphoproliferation in IL-2-deficient mice.
abstract: IL-2-deficient mice develop a lymphoproliferative and autoimmune disease characterized by autoimmune hemolytic anemia (AHA) and inflammatory bowel disease. We have previously reported that IL-2 is necessary for optimal up-regulation of CTLA-4, an inducible negative regulator of T cell activation. In this study, we have tested the hypothesis that reduced expression of CTLA-4 in IL-2-deficient T cells contributes to the pathogenesis of disease in IL-2-deficient mice. Expression of CTLA-4 as a transgene completely prevented lymphoaccumulation and AHA in IL-2-deficient mice. The normalization of T cell numbers was due to inhibition of expansion of conventional CD4+CD25- T cells rather than to rescue of the numbers or function of CD4+CD25+ regulatory T cells, suggesting that CTLA-4 expression on conventional T cells plays a role in maintaining normal T cell homeostasis. In addition, the inhibitory effect of the CTLA-4 transgene on T cell expansion was at least in part independent of CD28 expression. Our results suggest that deficient CTLA-4 expression on conventional T cells contributes to the pathophysiology of the lymphoproliferative disease and AHA in IL-2-deficient mice. Thus, restoring CTLA-4 expression in T cells may be an attractive strategy to control clinical autoimmune diseases in which CTLA-4 expression is reduced.
authors.affiliation: Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kwang Woo
authors.initials: KW
authors.lastname: Hwang
authors.forename: William B
authors.initials: WB
authors.lastname: Sweatt
authors.forename: Mona
authors.initials: M
authors.lastname: Mashayekhi
authors.forename: David A
authors.initials: DA
authors.lastname: Palucki
authors.forename: Hussain
authors.initials: H
authors.lastname: Sattar
authors.forename: Ellen
authors.initials: E
authors.lastname: Chuang
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Alegre
mesh_terms: D000744:Anemia, Hemolytic, Autoimmune / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D007376:Interleukin-2 / Q000172:deficiency* / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics*; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019076:Transgenes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D006131:Growth Inhibitors; D007376:Interleukin-2; D015375:Receptors, Interleukin-2