Differential modulation of CNS-specific effector and regulatory T cells during tolerance induction by recombinant invariant chains in vivo.
Inflammation within the Central Nervous System (CNS) is largely controlled by the balance between CNS-specific effector and regulatory T lymphocytes. To suppress CNS-inflammation in an antigen-specific manner, CNS-specific effector and regulatory T cells thus have to be differentially regulated. We employed recombinant peptide/MHC class II tetramers to assess CNS-specific effector and regulatory T cells during the specific suppression of myelin proteolipid protein aa139-151 (PLP139-151)-induced experimental autoimmune encephalomyelitis (EAE) by intravenous injection of recombinant invariant chains (Ii) in which the CLIP region has been replaced by the PLP139-151 epitope (Ii-PLP139-151). Injection of Ii-PLP139-151 induced apoptosis in CNS-specific effector T cells. In contrast, the proportion of specific regulatory T cells was increased and these cells expressed larger amounts of molecules that mediate regulatory T cell function including transforming growth factor beta and the inducible costimulator (ICOS). Consequently, regulatory T cells from Ii-treated mice were more potent than regulatory T cells from control-treated animals in suppressing effector T cell proliferation. These data demonstrate that effector T cells and regulatory T cells directed against the same CNS-antigen can be differentially regulated in vivo to suppress CNS-autoimmunity. Recombinant Ii induce apoptosis in CNS-specific effector T cells and provoke qualitative changes in specific regulatory T cells that enhance their immunosuppressive properties.
Hertie Institute for Clinical Brain Research, Department of General Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, Tübingen, Germany.
Christian
C
Lange
Hong
H
Doster
Karin
K
Steinbach
Hubert
H
Kalbacher
Matthias
M
Scholl
Arthur
A
Melms
Felix
F
Bischof
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D002490:Central Nervous System / Q000166:cytology* / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005434:Flow Cytometry; D005802:Genes, MHC Class II / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D011994:Recombinant Proteins; D053148:Caspase 3