Dendritic cells use endocytic pathway for cross-priming class Ib MHC-restricted CD8alphaalpha+TCRalphabeta+ T cells with regulatory properties.
Understanding the mechanisms leading to effective priming of lymphocytes with regulatory properties is crucial for the manipulation of immune responses. CD8alphaalpha(+)TCRalphabeta(+) T cells are a special subset of innate-like lymphocytes that have been shown to be involved in immune regulation. These cells can recognize self-peptides in the context of a class Ib molecule, Qa-1. How self-Ags are processed in the Qa-1 pathway and presented to CD8alphaalpha(+)TCRalphabeta(+) T cells is not understood. In this study we demonstrate a cross-presentation pathway by which bone marrow-derived dendritic cells (DCs) capture apoptotic CD4(+) T cells and process and present TCR-derived peptides in the context of Qa-1 to prime CD8alphaalpha(+)TCRalphabeta(+) T cells. The priming ability of the DCs is enhanced following TLR signaling using TLR3, TLR4, and TLR9 agonists. DC-mediated cross-presentation is inhibited in the presence of endosomal and proteasomal Ag-processing antagonists. Importantly, DCs loaded with apoptotic T cells prime CD8alphaalpha(+)TCRalphabeta(+) T cells in vivo, which in turn provides protection from CD4(+) T cell-mediated autoimmune disease. These data provide a key insight related to processing and presentation of self-Ags in the Qa-1 pathway for priming of CD8alphaalpha(+)TCRalphabeta(+) T cells and have implications for a DC-based immunotherapeutic approach to inflammatory diseases.
Smith
Trevor R F
TR
Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Tang
Xiaolei
X
Maricic
Igor
I
Garcia
Zacarias
Z
Fanchiang
Shaohsuan
S
Kumar
Vipin
V
D000818:Animals; D017209:Apoptosis; D001324:Autoantigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004705:Endocytosis / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta
D001324:Autoantigens; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D015395:Histocompatibility Antigens Class I; C032907:Q surface antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta