Cutting Edge: TLR Ligands Are Not Sufficient to Break Cross-Tolerance to Self-Antigens

Cross-presentation of peripheral self-Ags by dendritic cells (DC) can induce deletion of autoreactive CTL by a mechanism termed cross-tolerance. Activation of DC by microbial TLR ligands is thought to result in adaptive immunity. However, activation of tolerogenic DC may cause autoimmunity by stimul...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2005-02, Vol.174 (3), p.1159-1163
Main Authors: Hamilton-Williams, Emma E, Lang, Andreas, Benke, Dirk, Davey, Gayle M, Wiesmuller, Karl-Heinz, Kurts, Christian
Format: Article
Language:English
Subjects:
Adoptive Transfer
Animals
Autoantigens - immunology
CD8-Positive T-Lymphocytes - immunology
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Experimental - immunology
Insulin - genetics
Ligands
Lymphocyte Activation - immunology
Lymphocyte Count
Membrane Glycoproteins - metabolism
Membrane Glycoproteins - physiology
Mice
Mice, Knockout
Mice, Transgenic
Promoter Regions, Genetic - immunology
Rats
Receptors, Cell Surface - metabolism
Receptors, Cell Surface - physiology
Self Tolerance - immunology
Stem Cells - immunology
Stem Cells - pathology
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Helper-Inducer - immunology
T-Lymphocytes, Helper-Inducer - pathology
Toll-Like Receptor 2
Toll-Like Receptors
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Summary:Cross-presentation of peripheral self-Ags by dendritic cells (DC) can induce deletion of autoreactive CTL by a mechanism termed cross-tolerance. Activation of DC by microbial TLR ligands is thought to result in adaptive immunity. However, activation of tolerogenic DC may cause autoimmunity by stimulating instead of deleting autoreactive CTL. To investigate this scenario, we have monitored the response of autoreactive CTL in specific for the transgenic self Ag, OVA, expressed in pancreatic islets of RIP-mOVA mice injected with ligands of TLR2, 3, 4, and 9. This somewhat enhanced proliferation and cytokine production, and moderately reduced the CTL number able to induce autoimmunity. Nevertheless, physiological CTL numbers were deleted before disease ensued, unless specific CD4 T cell help was provided. In conclusion, DC activation by TLR ligands was insufficient to break peripheral cross-tolerance in the absence of specific CD4 T cell help, and triggered autoimmunity by stimulating the early effector phase of autoreactive CTL only when their precursor frequency was extremely high.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.174.3.1159