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* Cellular and Molecular Pathology Graduate Program,
Department of Pathology, University of Wisconsin, Madison, WI 53706; and
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792
Neuroinflammation often starts with the invasion of T lymphocytes into the CNS leading to recruitment of macrophages and amplification of inflammation. In this study, we show that dendritic cells (DCs) facilitate T-T cell help in the CNS and contribute to the amplification of local neuroinflammation. We adoptively transferred defined amounts of naive TCR-transgenic (TCR) recombination-activating gene-1-deficient T cells into another TCR-transgenic mouse strain expressing different Ag specificity. Following adoptive transfers, we coinjected DCs that presented one or multiple Ags into the brain and followed the activation of T cells with defined specificities simultaneously. Injection of DCs presenting both Ags simultaneously led to significantly higher infiltration of T cells into the brain compared with injection of a mixture of DCs pulsed with two Ags separately. DCs mediated either cooperative or competitive interactions between T cell populations with different specificities depending upon their MHC-restricting element usage. These results suggest that DC-mediated cooperation between brain-infiltrating T cells of different Ag specificities in the CNS plays an important role in regulation of neuroinflammation. This work also implies that blocking Ag-specific responses may block not only the targeted specificities, but may also effectively block their cooperative assistance to other T cells. Therefore, these data justify more attention to Ag-specific therapeutic approaches for neuroinflammation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01-NS 37570-01A2 (to Z.F.).
2 Current address: Department of Neurology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115.
3 Address correspondence and reprint requests to Dr. Zsuzsanna Fabry, Department of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Avenue, 6130 Medical Sciences Center, Madison, WI 53706. E-mail address: zfabry{at}wisc.edu
4 Abbreviations used in this paper: DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; PCC, pigeon cytochrome c; CA, chicken conalbumin; HEL, hen egg lysozyme; GFAP, glial fibrillary acidic protein; siRNA, short-inhibitory RNA.
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