title: T cells interact with T cells via CD40-CD154 to promote autoimmunity in type 1 diabetes.
abstract: We have investigated the role of CD40 signaling in islet-reactive, diabetogenic CD4(+)  Th1 T-cell clones. Using multispectral flow cytometry, we showed that CD40 and CD154 are co-expressed and form complexes on the surface of activated T cells. We also demonstrate that activated Tcells can transactivate CD4(+) CD40(+)  T cells through the CD40-CD154 pathway. To investigate the role of CD40 signaling on Th1 cells, we used the diabetogenic clone BDC-5.2.9 retrovirally transduced with a truncated form of the CD40 molecule to produce a CD40 dominant-negative T-cell clone. Upon challenge with antigen in vitro, the production of IFN-&&num;x003B3; by BDC-5.2.9 CD40DN was greatly reduced and, in vivo, the dominant-negative variant was unable to induce diabetes. Transduction with the CD40DN vector was also effective in preventing transfer of disease by primary NOD CD4(+)  T cells. Ex vivo analysis of pancreatic infiltrates after transfer of BDC-5.2.9 CD40DN cells revealed an overall reduction of cell numbers and cytokine production by both T cells and macrophages. These data indicate that CD40 is an important signaling molecule on autoreactive CD4(+)  T cells and contributes to their pathogenic effector function.
authors.affiliation: Integrated Department of Immunology, University of Colorado at Denver School of Medicine and National Jewish Health, Denver, CO 80206, USA.
authors.forename: Rocky L
authors.initials: RL
authors.lastname: Baker
authors.forename: Thierry
authors.initials: T
authors.lastname: Mallevaey
authors.forename: Laurent
authors.initials: L
authors.lastname: Gapin
authors.forename: Kathryn
authors.initials: K
authors.lastname: Haskins
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002999:Clone Cells; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D005434:Flow Cytometry; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D014161:Transduction, Genetic
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand