CD4؉ CD25 ؉ T cells are a population of regulatory T cells associated with control of arthritis in antiinterleukin-17 antibody-treated Borrelia-vaccinated and challenged gamma interferon-deficient mice. Here, we present direct evidence that adoptive transfer of enriched CD4 ؉ CD25 ؉ T cells from these mice can prevent the development of arthritis in Borrelia-vaccinated and challenged mice. These findings establish a major role for CD4؉ CD25 ؉ T cells in the prevention of arthritis in Borrelia-vaccinated and challenged animals.

We showed recently that the adaptive immune events leading to the development of arthritis in Borrelia burgdorferi isolate 297-vaccinated and Borrelia bissettiichallenged mice involve IL-17. Here, we show in Borrelia-vaccinated and -challenged mice that two cytokines known to induce the production of IL-17, IL-6 and transforming growth factor (TGF)-b, are also involved in the development of arthritis. Vaccinated and challenged mice administered either anti-TGF-b or anti-IL-6 antibodies developed histopathologic changes of the hind paws similar to or greater than untreated control mice. By contrast, simultaneous blockage of these cytokines reduced the severity of arthritis in Borrelia-vaccinated and -challenged mice. Moreover, administration of anti-IL-17 antibodies to these dual-antibodytreated mice completely prevented the development of histopathologic changes of the ankle joints, significantly reduced edema of the hind paws, and prevented the production of anti-outer surface protein A borreliacidal antibodies. These findings demonstrate a role for the combined effects of IL-17, IL-6, and TGF-b in the adaptive immune events leading to the development of Borrelia-induced arthritis.

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Determination of the immunological mediators responsible for promoting the production of borreliacidal antibody may facilitate the development of an improved borreliosis vaccine for human and veterinary use. Previously, we developed an in vitro assay to determine if borreliacidal antibody production could be augmented by treatment with different cytokines. In this study, in vitro treatment of lymph node cells producing borreliacidal antibody with recombinant interleukin-6 (rIL-6) resulted in a fourfold enhancement of anti-OspA borreliacidal antibody. Moreover, rIL-6 enhanced Western immunoblot titers and increased the number of B lymphocytes. In contrast, treatment of anti-OspA borreliacidal antibody-producing cells with anti-IL-6 resulted in a fourfold reduction in borreliacidal activity. Treatment with anti-IL-6 also inhibited enhanced borreliacidal antibody production induced by anti-gamma interferon. These data suggest that IL-6 plays a significant role in the production of anti-OspA borreliacidal antibodies.