ABSTRACT
Transgenic (Tg) mice that overexpress the costimulatory ligand B7.2/CD86 on microglia spontaneously develop a T cell-mediated demyelinating disease. Characterization of the inflammatory infiltrates in the nervous tissue revealed a predominance of CD8+ T cells, suggesting a prominent role of this T cell subset in the pathology. In this study, we show that the same neurological disease occurred in Tg mice deficient in the generation of CD4+ T cells, with an earlier time of onset. Analysis of the CD8+ T cell repertoire at early stage of disease revealed the presence of selected clonal expansions in the CNS but not in peripheral lymphoid organs. We further show that Tg animals deficient in IFN-gamma receptor expression were completely resistant to disease development. Microglia activation that is an early event in disease development is IFN-gamma dependent and thus appears as a key element in disease pathogenesis. Collectively, our data indicate that the spontaneous demyelinating disease in this animal model occurs as a consequence of an inflammatory response initiated through the activation of CNS-specific CD8+ T cells by Tg expression of B7.2 within the target organ. Thus, autoreactive CD8+ T cells can contribute directly to the pathogenesis of neuroinflammatory diseases such as multiple sclerosis.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Demyelinating Diseases/immunology , Demyelinating Diseases/pathology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Cells, Cultured , Demyelinating Diseases/genetics , Disease Models, Animal , Lymphopenia/genetics , Lymphopenia/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, TransgenicABSTRACT
In the present study, IFN-gamma exposure to primary cultures of rat type II epithelial cells (TIIP) upregulated membrane expression of the common gamma-chain of the IL-2 receptor (approximately 2.5- to 4-fold increase) and redistributed receptor affinity in TIIP, as assessed by Western blot, cell, and tissue histochemistry and Scatchard analysis. As for restitution processes of the lung epithelium, functionality of IL-2R on TIIP was conditional to IFN-gamma exposure: 1) IFN-gamma priming promoted a fivefold increase of IL-2-driven TIIP locomotion (P < 0.05 vs. control at 100 U/ml) and 2) IFN-gamma coincubation with IL-2 reduced bleomycin-induced TIIP apoptosis in vitro by 25% (caspase-3 activity) and by approximately 70% (TdT-mediated dUTP nick end labeling/4',6'-diamidino-2-phenylindole assay) as well as in vivo by approximately 90% (caspase-3 activity; P < 0.05 vs. control). Sustained p42/44 extracellular signal-regulated kinase activity played a protective role in this process, whereas specific inhibition by PD-98059 (50 microM) significantly reversed bleomycin-induced TIIP apoptosis (P < 0.05 vs. control). From these in vitro and in vivo data, it is proposed that combinations of IFN-gamma and IL-2 can drive repair activity of TIIP by stimulating migration and preventing programmed cell death, both of which are speculated to be very fast restitution events after oxidant-induced acute lung injury.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Movement/drug effects , Interferon-gamma/pharmacology , Interleukin-2/pharmacology , Respiratory Mucosa/cytology , Animals , Antimetabolites, Antineoplastic/pharmacology , Bleomycin/pharmacology , In Vitro Techniques , JNK Mitogen-Activated Protein Kinases , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinases/metabolism , Oxidative Stress/drug effects , Oxidative Stress/physiology , Phosphorylation , Rats , Receptors, Interleukin-2/metabolism , Respiratory Mucosa/metabolism , Up-Regulation/drug effects , p38 Mitogen-Activated Protein KinasesABSTRACT
It has been proposed that the activation status of antigen-presenting cells (APCs) plays a significant role in the development of autoimmune disease. Whether expression of costimulatory ligands on tissue-resident APCs controls organ-specific autoimmune responses has not been tested. We here report that transgenic mice constitutively expressing the costimulatory ligand B7.2/CD86 on microglia in the central nervous system (CNS) and on related cells in the proximal peripheral nervous tissue spontaneously develop autoimmune demyelinating disease. Disease-affected nervous tissue in transgenic mice showed infiltration characterized by a predominance of CD8+ memory-effector T cells, as well as CD4+ T cells. Transgenic animals lacking alphabeta TCR+ T cells were completely resistant to disease development. Transgenic T cells induced disease when adoptively transferred into T cell-deficient B7.2 transgenic recipients but not into non-transgenic recipients. These data provide evidence that B7/CD28 interactions within the nervous tissue are critical determinants of disease development. Our findings have important implications for understanding the etiology of nervous system autoimmune diseases such as multiple sclerosis (MS) and Guillain-Barré syndrome (GBS).
