ABSTRACT
Adhesion molecules are believed to facilitate infiltration of leukocytes into the CNS of mice with experimental allergic encephalomyelitis (EAE). The role of the adhesion molecule CD62L (L-selectin) in the immunopathology of EAE is not known. To study this, we crossed CD62L-deficient mice with myelin basic protein-specific TCR (MBP-TCR) transgenic mice. CD62L-deficient MBP-TCR transgenic mice failed to develop antigen-induced EAE, and, despite the presence of leukocyte infiltration, damage to myelin in the CNS was not seen. EAE could, however, be induced in CD62L-deficient mice upon adoptive transfer of wild-type macrophages. Our results suggest that CD62L is not required for activation of autoimmune CD4 T cells but is important for the final destructive function of effector cells in the CNS and support a novel mechanism whereby CD62L expressed on effector cells is important in mediating myelin damage.
Subject(s)
Central Nervous System/metabolism , Encephalomyelitis, Autoimmune, Experimental/metabolism , Encephalomyelitis, Autoimmune, Experimental/pathology , L-Selectin/metabolism , Myelin Sheath/pathology , Adoptive Transfer , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Antigen-Presenting Cells/transplantation , Autoimmunity/genetics , Autoimmunity/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/transplantation , Cell Adhesion , Central Nervous System/pathology , Chemotaxis, Leukocyte , Gene Deletion , Immunohistochemistry , L-Selectin/genetics , Lymphocyte Activation , Macrophages/immunology , Macrophages/metabolism , Macrophages/transplantation , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myelin Basic Protein/genetics , Myelin Basic Protein/immunology , Myelin Basic Protein/metabolism , Myelin Sheath/metabolism , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Recombinant Fusion Proteins/metabolismABSTRACT
Lately, TNF alpha has been the focus of studies of autoimmunity; its role in the progression of autoimmune diabetes is, however, still unclear. To analyze the effects of TNF alpha in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNF alpha under the control of the rat insulin II promoter (RIP). In transgenic mice, TNF alpha expression on the islets resulted in massive insulitis, composed of CD4+ T cells, CD8+ T cells, and B cells. Despite infiltration of considerable number of lymphoid cells in islets, expression of TNF alpha protected NOD mice from IDDM. To determine the mechanism of TNF alpha action, splenic cells from control NOD and RIP-TNF alpha mice were adoptively transferred to NOD-SCID recipients. In contrast to the induction of diabetes by splenic cells from control NOD mice, splenic cells from RIP-TNF alpha transgenic mice did not induce diabetes in NOD-SCID recipients. Diabetes was induced however, in the RIP-TNF alpha transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNF alpha in islets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNF alpha action and provide evidence that local expression of TNF alpha protects NOD mice from autoimmune diabetes by preventing the development of autoreactive islet-specific T cells.
Subject(s)
Autoimmunity/drug effects , Diabetes Mellitus, Type 1/prevention & control , Islets of Langerhans/immunology , T-Lymphocytes/drug effects , Tumor Necrosis Factor-alpha/therapeutic use , Adoptive Transfer , Animals , Cell Movement , Diabetes Mellitus, Type 1/immunology , Female , Glucagon/isolation & purification , Glutamate Decarboxylase/immunology , Immune Tolerance , Insulin/genetics , Insulin/isolation & purification , Leukocytes, Mononuclear , Lymphoid Tissue/drug effects , Male , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Pancreatitis/pathology , Peptide Fragments/immunology , Promoter Regions, Genetic , Rats , Recombinant Fusion Proteins/therapeutic use , Sex Characteristics , Spleen/cytology , Spleen/immunology , Tumor Necrosis Factor-alpha/geneticsABSTRACT
The mechanism of CD40 ligand (CD40L)-mediated in vivo activation of CD4(+) T cells was examined by investigation of the development of experimental allergic encephalomyelitis (EAE) in CD40L-deficient mice that carried a transgenic T cell receptor specific for myelin basic protein. These mice failed to develop EAE after priming with antigen, and CD4(+) T cells remained quiescent and produced no interferon-gamma (IFN-gamma). T cells were primed to make IFN-gamma and induce EAE by providing these mice with B7.1(+) antigen-presenting cells (APCs). Thus, CD40L is required to induce costimulatory activity on APCs for in vivo activation of CD4(+) T cells to produce IFN-gamma and to evoke autoimmunity.
