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 re ceptor for monocyte chemoattractant protein-1, have markedly impaired recru itment of macrophages to sites of inflammation. An unexpected finding in th e CCR2(-/-) mice was a dramatic decrease in the production of IFN-gamma aft er challenge with purified protein derivative of Mycobacterium bovis. In th is study, we have investigated the mechanism of this cytokine production de fect. In vitro, direct activation of splenocytes with CD3/CD28 Abs failed t o reveal any differences in IFN-gamma production between CCR2(+/+) and CCR2 (-/-) mice. However, after immunization, the number of Ag-specific, IFN-gam ma -producing cells in the draining lymph nodes was decreased by 70% in the CCR2(-/-) mice, suggesting an in vivo trafficking defect, Direct measureme nt of cell trafficking with fluorescently labeled CFA revealed a marked dec rease in the number of monocytes/macrophages migrating to the site of immun ization and to the draining lymph nodes in the CCR2(-/-)mice. The data sugg est that impaired trafficking of APCs in the CCR2(-/-) mice contributes to the defect in IFN-gamma production, These data support the idea that CCR2-p ositive monocytes/macrophages are critical in linking the innate and adapti ve immune responses.