Ligand-Dependent Induction of Noninflammatory Dendritic Cells by Anergic Invariant NKT Cells Minimizes Autoimmune Inflammation

• Published in: The Journal of immunology (1950) Vol. 181; no. 4; pp. 2438 - 2445
• Main Authors: Wang, Jianxiong, Cho, Suzanne, Ueno, Aito, Cheng, Lu, Xu, Bo-You, Desrosiers, Melanie D, Shi, Yan, Yang, Yang
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.08.2008
• Subjects: Animals; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Autoimmune Diseases - prevention & control; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation - immunology; Clonal Anergy; Dendritic Cells - cytology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes Mellitus, Type 1 - prevention & control; Dose-Response Relationship, Immunologic; Galactosylceramides - administration & dosage; Immunophenotyping; Inflammation - immunology; Inflammation - pathology; Inflammation - prevention & control; Islets of Langerhans - immunology; Islets of Langerhans - pathology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Ligands; Lymphocyte Activation - immunology; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, Transgenic; Self Tolerance - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.4.2438

Stimulated by an agonistic ligand, alpha-galactosylceramide (alphaGalCer), invariant NKT (iNKT) cells are capable of both eliciting antitumor responses and suppressing autoimmunity, while they become anergic after an initial phase of activation. It is unknown how iNKT cells act as either activators or regulators in different settings of cellular immunity. We examined effects of alphaGalCer administration on autoimmune inflammation and characterized phenotypes and functional status of iNKT cells and dendritic cells in alphaGalCer-treated NOD mice. Although iNKT cells became and remained anergic after the initial exposure to their ligand, anergic iNKT cells induce noninflammatory DCs in response to alphaGalCer restimulation, whereas activated iNKT cells induce immunogenic maturation of DCs in a small time window after the priming. Induction of noninflammatory DCs results in the activation and expansion of islet-specific T cells with diminished proinflammatory cytokine production. The noninflammatory DCs function at inflammation sites in an Ag-specific fashion, and the persistence of noninflammatory DCs critically inhibits autoimmune pathogenesis in NOD mice. Anergic differentiation is a regulatory event that enables iNKT cells to transform from promoters to suppressors, down-regulating the ongoing inflammatory responses, similar to other regulatory T cells, through a ligand-dependent mechanism.