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Production in C-C Chemokine Receptor 2 (CCR2) Knockout Mice: Role of CCR2 in Linking the Innate and Adaptive Immune Responses1
,§
*
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94141; and
Cardiovascular Research Institute,
Department of Anatomy, and
§
Department of Medicine, University of California, San Francisco, CA 94143
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-
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- production
between CCR2+/+ and
CCR2-/- mice. However, after immunization,
the number of Ag-specific, IFN--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- production. These data support the idea that CCR2-positive
monocytes/macrophages are critical in linking the innate and adaptive
immune responses.
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