Targeted overexpression of IL-18 binding protein at the central nervous system overrides flexibility in functional polarization of antigen-specific Th2 cells.
The current study shows that functional polarization of Ag-specific CD4(+) Th2 cells entering the CNS during the accelerating phase of experimental autoimmune encephalomyelitis is flexible and dependent on the cytokine milieu there. Thus, targeted cell/gene therapy by Ag-specific T cells overexpressing IL-18 binding protein overrides this flexibility and induces infectious spread of T cell tolerance. Using a congenic system, we demonstrated that at this time, Ag-specific Th2 cells accumulate at the CNS but then arrest of IL-4 production. A manipulation of targeted cell/gene delivery was then used to detect whether this function is dependent on the cytokine milieu there. Targeted overexpression of IL-18 binding protein, a natural inhibitor of IL-18, restored the ability of these Ag-specific Th2 cells to produce IL-4 and subsequently induce protective spread of Th2 polarization. These findings not only suggest a novel way of therapy, but also explain why shifting the balance of Ag-specific T cells toward Th2 suppresses ongoing experimental autoimmune encephalomyelitis, whereas a direct transfer of these cells is ineffective.
Schif-Zuck
Sagie
S
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Westermann
Juergen
J
Netzer
Nir
N
Zohar
Yaniv
Y
Meiron
Moran
M
Wildbaum
Gizi
G
Karin
Nathan
N
D000818:Animals; D002490:Central Nervous System / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology; D007108:Immune Tolerance; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein; D015847:Interleukin-4