These results indicate that CD4 +CD25 + regulatory T cells can act in an antigen-specific manner in vivo. Importantly, in mice injected with a mix of target and third-party bone-marrows, protection and rejection processes took place simultaneously. Here we show that CD4 +CD25 + regulatory T lymphocytes isolated from naive mice and activated in vitro with allogeneic APC, induced specific long-term tolerance to bone-marrow grafts disparate for major and minor histocompatibility antigens : Whereas “target” bone-marrow was protected, third-party bone-marrow was rejected. In vivo, regulatory T cells are also activated in an antigen-specific fashion, but nothing is known about antigen-specificity of their suppressor effector function. In vitro, CD4 +CD25 + T cells require specific MHC/peptide ligands for their activation, but once activated they act in an antigen-non-specific manner. Thymus-derived regulatory T lymphocytes of CD4 +CD25 + phenotype regulate a large variety of beneficial and deleterious immune-responses and can inhibit lethal graft-versus-host disease in rodents.
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