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

• 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.3.1159

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.