Ectopic T-cell specificity and absence of perforin and granzyme B alleviate neural damage in oligodendrocyte mutant mice. Am J Pathol 2010 Feb;176(2):549-55
Date
01/01/2010Pubmed ID
20042681Pubmed Central ID
PMC2808063DOI
10.2353/ajpath.2010.090722Scopus ID
2-s2.0-76149091902 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
In transgenic mice overexpressing the major myelin protein of the central nervous system, proteolipid protein, CD8+ T-lymphocytes mediate the primarily genetically caused myelin and axon damage. In the present study, we investigated the cellular and molecular mechanisms underlying this immune-related neural injury. At first, we investigated whether T-cell receptors (TCRs) are involved in these processes. For this purpose, we transferred bone marrow from mutants carrying TCRs with an ectopic specificity to ovalbumin into myelin mutant mice that also lacked normal intrinsic T-cells. T-lymphocytes with ovalbumin-specific TCRs entered the mutant central nervous system to a similar extent as T-lymphocytes from wild-type mice. However, as revealed by histology, electron microscopy and axon- and myelin-related immunocytochemistry, these T-cells did not cause neural damage in the myelin mutants, reflecting the need for specific antigen recognition by cytotoxic CD8+ T-cells. By chimerization with bone marrow from perforin- or granzyme B (Gzmb)-deficient mice, we demonstrated that absence of these cytotoxic molecules resulted in reduced neural damage in myelin mutant mice. Our study strongly suggests that pathogenetically relevant immune reactions in proteolipid protein-overexpressing mice are TCR-dependent and mediated by the classical components of CD8+ T-cell cytotoxicity, perforin, and Gzmb. These findings have high relevance with regard to our understanding of the pathogenesis of disorders primarily caused by genetically mediated oligodendropathy.
Author List
Kroner A, Ip CW, Thalhammer J, Nave KA, Martini RAuthor
Antje Kroner-Milsch PhD, MD Associate Professor in the Neurosurgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD8-Positive T-Lymphocytes
Cells, Cultured
Central Nervous System
Demyelinating Autoimmune Diseases, CNS
Genes, RAG-1
Granzymes
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Myelin Proteolipid Protein
Neurons
Oligodendroglia
Organ Specificity
Perforin
T-Cell Antigen Receptor Specificity
