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Hamsters receiving both macrophages exposed to Formalin-inactivated Borrelia burgdorferi (Mphi-FBb) and enriched populations of either immune or naive T lymphocytes developed severe swelling of the hind paws when infected with B. burgdorferi. Swelling was detected 6 days after infection, peaked on day 10, and gradually decreased. Swelling was also observed in the hind paws of hamsters infused with only Mphi-FBb or only enriched populations of either immune or naive T lymphocytes after infection with B. burgdorferi. However, the swelling detected in these hamsters was less severe and of shorter duration. In addition, hamsters receiving both macrophages not exposed to Formalin-inactivated B. burgdorferi (Mphi-NFBb) and enriched populations of either immune or naive T lymphocytes failed to develop severe swelling after infection with B. burgdorferi. No swelling was also observed in hamsters infused with both Mphi-FBb and enriched populations of immune T lymphocytes and then inoculated with spirochetal growth medium. We further showed that macrophages and enriched populations of T lymphocytes did not interact synergistically for controlling B. burgdorferi infection, as spirochetes were readily recovered from the tissues of all cell transfer recipients infected with B. burgdorferi. These findings demonstrate that hamsters infused with both Mphi-FBb and enriched populations of either immune or naive T lymphocytes develop a more fulminate arthritis after infection with B. burgdorferi than recipients infused with either cell type alone. These findings suggest that macrophages and T lymphocytes interact synergistically for the induction of severe, destructive Lyme arthritis.