Rebuilding an immune-mediated central nervous system disease: weighing the pathogenicity of antigen-specific versus bystander T cells.
Although both self- and pathogen-specific T cells can participate in tissue destruction, recent studies have proposed that after viral infection, bystander T cells of an irrelevant specificity can bypass peptide-MHC restriction and contribute to undesired immunopathological consequences. To evaluate the importance of this mechanism of immunopathogenesis, we determined the relative contributions of Ag-specific and bystander CD8+ T cells to the development of CNS disease. Using lymphocytic choriomeningitis virus (LCMV) as a stimulus for T cell recruitment into the CNS, we demonstrate that bystander CD8+ T cells with an activated surface phenotype can indeed be recruited into the CNS over a chronic time window. These cells become anatomically positioned in the CNS parenchyma, and a fraction aberrantly acquires the capacity to produce the effector cytokine, IFN-gamma. However, when directly compared with their virus-specific counterparts, the contribution of bystander T cells to CNS damage was insignificant in nature (even when specifically activated). Although bystander T cells alone failed to cause tissue injury, transferring as few as 1000 naive LCMV-specific CD8+ T cells into a restricted repertoire containing only bystander T cells was sufficient to induce immune-mediated pathology and reconstitute a fatal CNS disease. These studies underscore the importance of specific T cells in the development of immunopathology and subsequent disease. Because of highly restrictive constraints imposed by the host, it is more likely that specific, rather than nonspecific, bystander T cells are the active participants in T cell-mediated diseases that afflict humans.
Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, La Jolla, CA 92037, USA. mcgad@scripps.edu
Dorian B
DB
McGavern
Phi
P
Truong
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D016207:Cytokines / Q000096:biosynthesis; D006183:H-2 Antigens / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D018960:Hyaluronan Receptors / Q000032:analysis; D008216:Lymphocytic Choriomeningitis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D018960:Hyaluronan Receptors; D010446:Peptide Fragments