C-C chemokine receptor regulates the antibody response to DNP-KLH

Abstract Functional loss of C-C chemokine receptor 7 (CCR7) and its ligands, CCL19 and CCL21, has been linked to development of autoimmune diseases. Therefore, we hypothesized that CCR7 antagonists could be used to promote an immune response that could be measured by tittering antibodies produced in animals injected with test antigens. To test this hypothesis we injected C57BL/6 mice on day 0 and boosted on day 20 with dinitrophenol (DNP)-Keyhole Limpet Hemocyanin (KLH) with a CCL19 antagonist, 8-83, or with the agonist solvent as a control. Similar to the CCR7-/- mouse, which has significantly elevated levels of IgG1, IgG2a, IgG2b and IgG3 by day 30, the animals treated with 8-83 generated significantly higher levels of IgG1 and IgG2a, than animals injected with the DNP-KLH/solvent alone. Previous studies by our laboratory have shown that CCL19 signals through ERK5. To determine if loss of signaling through ERK induced a similar increase in the levels of IgGs, we injected ERK5flox/flox control mice or ERK5flox/floxLck-Cre mice with DNP-KLH. Similar to animals treated with 8-83, the ERK5flox/flox Lck-Cre mice produced significantly higher levels of IgG1, IgG2a and IgG3 than control mice. From these results we conclude that CCR7/CCL19 signals through ERK5 to control the levels of antibodies made. Recent studies demonstrating a role for CCR7 in controlling the localization of regulatory T cells may provide insight into immune cells that are regulate observed increase in antibody titers.