Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis.
Recruitment of naturally occurring CD4+ CD25+ regulatory T (T(reg)) 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 T(reg) 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 T(reg) 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 T(reg) cells in the spinal cord. However, the delayed homing to the CNS seen after prophylactic JJ316 administration indicates that T(reg) 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 T(H)2 cytokines was augmented and the encephalitogenic T cells exhibited a reduced secretion of IFN-gamma. 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 T(reg) 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 T(reg) cells in controlling autoimmunity in the CNS.
Tischner
Denise
D
Institute for Virology and Immunobiology, University of Würzburg, Germany.
Weishaupt
Andreas
A
van den Brandt
Jens
J
Müller
Nora
N
Beyersdorf
Niklas
N
Ip
Chi Wang
CW
Toyka
Klaus V
KV
Hünig
Thomas
T
Gold
Ralf
R
Kerkau
Thomas
T
Reichardt
Holger M
HM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D018106:CD28 Antigens / Q000276:immunology*; D002465:Cell Movement; D049109:Cell Proliferation; D005434:Flow Cytometry; D007116:Immunization, Passive / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D018613:Microscopy, Confocal; D023421:Models, Animal; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology; D013116:Spinal Cord / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; C515189:Cxcr3 protein, rat; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D007371:Interferon-gamma