Release of dendritic cells from cognate CD4⁺ T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 23; pp. 9059 - 9064
• Main Authors: Muth, Sabine, Schütze, Kristian, Schild, Hansjörg, Probst, Hans Christian
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.06.2012; National Acad Sciences
• Subjects: Adaptive Immunity - immunology; Animals; Autoimmune diseases; Autoimmunity; Autoimmunity - immunology; Biological Sciences; Body Weight; Cells; Chimeras; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Exercise tolerance; Flow Cytometry; Genes, MHC Class II - genetics; Genes, MHC Class II - immunology; Genotype & phenotype; Histological Techniques; Homeodomain Proteins; Immune tolerance; Immunity (Disease); Lymphocyte Activation - immunology; Lymphocytes; Mice; Mice, Transgenic; Peripheral Tolerance - immunology; Rodents; Spleen; T lymphocytes; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Regulatory - immunology; Tamoxifen; Transplantation tolerance
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1110620109

Resting dendritic cells (DCs) induce tolerance of peripheral T cells that have escaped thymic negative selection and thus contribute significantly to protection against autoimmunity. We recently showed that CD4⁺Foxp3⁺ regulatory T cells (Tregs) are important for maintaining the steady-state phenotype of DCs and their tolerizing capacity in vivo. We now provide evidence that DC activation in the absence of Tregs is a direct consequence of missing DC-Treg interactions rather than being secondary to generalized autoimmunity in Treg-less mice. We show that DCs that lack MHC class II and thus cannot make cognate interactions with CD4⁺ T cells are completely unable to induce peripheral CD8⁺ T-cell tolerance. Consequently, mice in which interactions between DC and CD4⁺ T cells are not possible develop spontaneous and fatal cytotoxic T lymphocyte-mediated autoimmunity.