ABSTRACT
We investigated the in vivo function of the B7 family member B7-H3 (also known as B7RP-2) by gene targeting. B7-H3 inhibited T cell proliferation mediated by antibody to T cell receptor or allogeneic antigen-presenting cells. B7-H3-deficient mice developed more severe airway inflammation than did wild-type mice in conditions in which T helper cells differentiated toward type 1 (T(H)1) rather than type 2 (T(H)2). B7-H3 expression was consistently enhanced by interferon-gamma but suppressed by interleukin 4 in dendritic cells. B7-H3-deficient mice developed experimental autoimmune encephalomyelitis several days earlier than their wild-type littermates, and accumulated higher concentrations of autoantibodies to DNA. Thus, B7-H3 is a negative regulator that preferentially affects T(H)1 responses.
Subject(s)
B7-1 Antigen/immunology , Th1 Cells/immunology , Animals , Autoantibodies/immunology , Autoantibodies/metabolism , B7 Antigens , B7-1 Antigen/biosynthesis , Dendritic Cells/immunology , Dendritic Cells/metabolism , Down-Regulation/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Flow Cytometry , Interferon-gamma/immunology , Interleukin-4/immunology , Lymphocyte Activation/immunology , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae/immunology , Receptors, Antigen, T-Cell/immunology , Vesicular stomatitis Indiana virus/immunologyABSTRACT
Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.
