A mechanism for the impaired IFN-gamma production in C-C chemokine receptor 2 (CCR2) knockout mice: role of CCR2 in linking the innate and adaptive immune responses.
We have recently shown that mice with a targeted disruption of CCR2, the receptor for monocyte chemoattractant protein-1, have markedly impaired recruitment of macrophages to sites of inflammation. An unexpected finding in the CCR2(-/-) mice was a dramatic decrease in the production of IFN-gamma after challenge with purified protein derivative of Mycobacterium bovis. In this study, we have investigated the mechanism of this cytokine production defect. In vitro, direct activation of splenocytes with CD3/CD28 Abs failed to reveal any differences in IFN-gamma production between CCR2(+/+) and CCR2(-/-) mice. However, after immunization, the number of Ag-specific, IFN-gamma-producing cells in the draining lymph nodes was decreased by 70% in the CCR2(-/-) mice, suggesting an in vivo trafficking defect. Direct measurement of cell trafficking with fluorescently labeled CFA revealed a marked decrease in the number of monocytes/macrophages migrating to the site of immunization and to the draining lymph nodes in the CCR2(-/-) mice. The data suggest that impaired trafficking of APCs in the CCR2(-/-) mice contributes to the defect in IFN-gamma production. These data support the idea that CCR2-positive monocytes/macrophages are critical in linking the innate and adaptive immune responses.
Peters
W
W
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94141, USA.
Dupuis
M
M
Charo
I F
IF
D000222:Adaptation, Physiological / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018106:CD28 Antigens / Q000494:pharmacology; D017252:CD3 Complex / Q000494:pharmacology; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005620:Freund's Adjuvant / Q000008:administration & dosage; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; C515335:Ccr2 protein, mouse; D018984:Epitopes, T-Lymphocyte; D008070:Lipopolysaccharides; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D003208:Concanavalin A; D007371:Interferon-gamma; D005620:Freund's Adjuvant; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin