Impaired macrophage function and enhanced T cell-dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor.
The CC-chemokine receptor CCR5 has been shown to be the major coreceptor for HIV-1 entry into cells, and humans with homozygous mutation in the ccr5 gene are highly resistant to HIV-1 infection, despite the existence of many other HIV-1 coreceptors. To investigate the physiologic function of CCR5 and to understand the cellular mechanisms of these clinical observations, we generated a CCR5-deficient mouse model (ccr5[-/-]) by targeted deletion of the ccr5 gene. We found that although developed normally in a pathogen-free environment, CCR5-deficient mice showed reduced efficiency in clearance of Listeria infection and exert a protective effect against LPS-induced endotoxemia, reflecting a partial defect in macrophage function. In addition, CCR5-deficient mice had an enhanced delayed-type hypersensitivity reaction and increased humoral responses to T cell-dependent antigenic challenge, indicating a novel role of CCR5 in down-modulating T cell-dependent immune response.
Zhou
Y
Y
Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Kurihara
T
T
Ryseck
R P
RP
Yang
Y
Y
Ryan
C
C
Loy
J
J
Warr
G
G
Bravo
R
R
D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D016207:Cytokines / Q000096:biosynthesis; D018390:Gene Targeting; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D006968:Hypersensitivity, Delayed; D007074:Immunoglobulin G / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015728:Receptors, HIV / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014115:Toxemia / Q000209:etiology / Q000276:immunology
D000941:Antigens; D016207:Cytokines; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D019713:Receptors, CCR5; D015728:Receptors, HIV