Regulation of viral and autoimmune responses.
We have studied the induction and effector function of Th2-like regulatory cells in mouse models for type 1 diabetes (NOD and RIP-LCMV). CD4+ lymphocytes with specificity for insulin can be induced by immunization with the insulin B chain via the oral route or by DNA vaccination. Such cells are protective upon adoptive transfer and prevent diabetes development in syngeneic pre-diabetic recipients. In comparison to non-regulatory insulin B-specific cell lines, they produce high amounts of interleukin (IL)4 and IL10, whereas interferon (IFN)gamma and tumour necrosis factor (TNF)alpha levels are comparable. Indeed, IL4 is essential for the protective capability, as evidenced by use of IL4-deficient mice and sorting of IL4+ versus IL4- lymphocytes prior to transfer. Mechanistically, these cells act as bystander suppressors in the pancreatic draining node, the location where their cognate antigen, insulin B, is presented during the pre-diabetic inflammatory process. As a consequence, the autoaggressive response is locally dampened. We propose that this is achieved by modulation of antigen presenting cells that lose the ability to propagate aggressive responses after exposure to IL4 or IL10 in vitro. The clinically attractive side of our strategy is that it only acts as the site of inflammation, thus circumventing systemic side effects. In order to avoid induction of insulin B-specific autoaggressive T cells we have demonstrated that administration of IL4 or IL10 at the time of immunization is beneficial and therefore should be part of a potential future clinical application. Interestingly, these Th2-like regulators share in our systems no features with the so-called CD25+ regulatory cells, whose antigen specificity is still unclear. However, we have recent evidence that virus specific CD25+ cells can be generated and are able to affect antiviral responses in vivo.
Asseman
Chrystelle
C
La Jolla Institute for Allergy and Immunology, Division of Immune Regulation, 10355, Science Center Drive, San Diego, CA 92121, USA.
von Herrath
Matthias
M
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D004195:Disease Models, Animal; D006706:Homeostasis / Q000276:immunology; D007328:Insulin / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; D007328:Insulin