Differential modulation of CNS-specific effector and regulatory T cells during tolerance induction by recombinant...

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encephalomyelitis (EAE) by intravenous injection of recombinant invariant chains (Ii) in which the CLIP region has been replaced by the PLP139-151 epitope (Ii-PLP139-151).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.