Brain Advance Access originally published online on August 18, 2006
Brain 2006 129(10):2635-2647; doi:10.1093/brain/awl213
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Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis
1 Institute for Virology and Immunobiology, University of Würzburg Germany 2 Department of Neurology, Clinical Research Unit for Multiple Sclerosis and Neuroimmunology University of Würzburg, Germany 3 Institute for Multiple Sclerosis Research, Medical Faculty and Gemeinnützige Hertie-Stiftung University of Göttingen, Germany
Correspondence to: Prof. Dr Holger Reichardt, Institute for Virology and Immunobiology, University of Würzburg, Germany and Prof. Dr Ralf Gold, Institute for Multiple Sclerosis Research, Medical Faculty and Gemeinnützige Hertie-Stiftung, University of Göttingen, Germany E-mail: holger.reichardt{at}mail.uni-wuerzburg.de; r.gold{at}med.uni-goettingen.de
Recruitment of naturally occurring CD4+ CD25+ regulatory T (Treg) cells is a highly promising approach for the treatment of experimental autoimmune encephalomyelitis (EAE), a widely used model of multiple sclerosis. Here, we studied the in vivo interaction of Treg cells, induced by the monoclonal anti-CD28 antibody JJ316, with encephalitogenic T cell lines established from eGFP-transgenic rats. By tracking these fluorescent cells using flow cytometry and confocal microscopy, we found that the activation and expansion of Treg cells inhibited infiltration of the CNS by pathogenic T cells. Interference with effector cell migration occured within the secondary lymphoid organs, since the early therapeutic effects were achieved despite the absence of Treg cells in the spinal cord. However, the delayed homing to the CNS seen after prophylactic JJ316 administration indicates that Treg cells may play an additional role within the target tissue. In addition, the blood–brain barrier remained largely intact after JJ316 treatment, the secretion of TH2 cytokines was augmented and the encephalitogenic T cells exhibited a reduced secretion of IFN-
. This in turn resulted in a reduced expression of the chemokine receptor CXCR-3 on effector T cells which may interfere with their capacity to infiltrate the CNS. Importantly, these effects were not achieved by direct action of JJ316 on the encephalitogenic cells. Our data rather suggest that polyclonal activation of Treg cells in the secondary lymphoid organs is instrumental in preventing the pathological transmigration of encephalitogenic T cells into the CNS. We anticipate that these results may help to better understand the role of Treg cells in controlling autoimmunity in the CNS.
Key Words: experimental autoimmune encephalomyelitis; immunotherapy; regulatory T cells; cell migration; CXCR-3
Abbreviations: AT-EAE, adoptive transfer EAE; BBB, blood–brain barrier; EAE, experimental autoimmune encephalomyelitis; Tconv, conventional CD4+ T cells; Treg cells, regulatory T cells
Received April 7, 2006. Revised June 21, 2006. Accepted July 19, 2006.
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