title: Modulation of murine Lyme borreliosis by interruption of the B7/CD28 T-cell costimulatory pathway.
abstract: 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 molecules CD80 and CD86 to the Th2 cytokine profile and development of arthritis in BALB/c mice infected with Borrelia burgdorferi. Effective blockade of CD86/CD28 interaction was demonstrated by elimination of interleukin 4 (IL-4) and upregulation of gamma interferon (IFN-gamma) responses by B. burgdorferi-specific T cells and by reduction of B. burgdorferi-specific immunoglobulin G. Despite the shift toward a Th1 cytokine pattern, which others have associated with disease susceptibility, the severity of arthritis was unchanged. Moreover, combined CD80/CD86 blockade by using anti-CD80 and anti-CD86 monoclonal antibodies or CTLA-4Ig enhanced IFN-gamma production over that seen with CD86 blockade alone, 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 interaction and that this cytokine does not contribute significantly to host resistance to the development of arthritis. In addition, combined CD80/CD86 blockade resulted in preferential expansion of IFN-gamma-producing T cells in B. burgdorferi infection, suggesting that costimulatory pathways other than B7/CD28 may contribute to T-cell activation during continuous antigen stimulation. These studies may provide insight into the role of the B7/CD28 pathway in other infectious and autoimmune diseases in which deviation of Th cell immune responses occurs and antigen is persistently present.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. Linda.Bockenstedt@Yale.edu
authors.forename: M C
authors.initials: MC
authors.lastname: Shanafelt
authors.forename: I
authors.initials: I
authors.lastname: Kang
authors.forename: S W
authors.initials: SW
authors.lastname: Barthold
authors.forename: L K
authors.initials: LK
authors.lastname: Bockenstedt
mesh_terms: D000069594:Abatacept; D000818:Animals; D000907:Antibodies, Bacterial / Q000378:metabolism; D019138:Antibodies, Blocking / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology; D001170:Arthritis, Infectious / Q000276:immunology* / Q000382:microbiology; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D005260:Female; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008193:Lyme Disease / Q000276:immunology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013047:Specific Pathogen-Free Organisms; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000907:Antibodies, Bacterial; D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D015847:Interleukin-4; D000069594:Abatacept; D007371:Interferon-gamma