MODULATION OF MURINE LYME BORRELIOSIS BY INTERRUPTION OF THE B7 CD28 T-CELL COSTIMULATORY PATHWAY/

Recent studies have implicated cytokines associated with Th2 cells in the genetic resistance to murine Lyme borreliosis. Because the B7/CD28 costimulatory pathway has been shown to influence the differentiation of Th-cell subsets, we investigated the contribution of the B7 molecu les CD80 and CD86 to the Th2 cytokine profile and development of arthr itis in BALB/c mice infected with Borrelia burgdorferi. Effective bloc kade of CD86/CD28 interaction was demonstrated by elimination of inter leukin I (IL-4) and upregulation of gamma interferon (IFN-gamma) respo nses by B. burgdorferi-specific T cells and by reduction of B, burgdor feri-specific immunoglobulin G. Despite the shift toward a Th1 cytokin e pattern, which others have associated with disease susceptibility, t he severity of arthritis was unchanged, Moreover, combined CD80/CD86 b lockade by using anti-CD80 and anti-CD86 monoclonal antibodies or CTLA -4Ig enhanced IFN-gamma production over that seen with CD86 blockade a lone, yet augmentation of this Th1-associated cytokine did not enhance disease. These results demonstrate that IL-4 production by T cells in B. burgdorferi-infected BALB/c mice is dependent upon CD86/CD28 inter action and that this cytokine does not contribute significantly to hos t resistance to the development of arthritis, In addition, combined CD 80/CD86 blockade resulted in preferential expansion of IFN-gamma-produ cing T cells in B. burgdorferi infection, suggesting that costimulator y pathways other than B7/CD28 may contribute to T-cell activation duri ng continuous antigen stimulation, These studies may provide insight i nto the role of the B7/CD28 pathway in other infectious and autoimmune diseases in which deviation of Th cell immune responses occurs and an tigen is persistently present.