Antigen-Specific Immune Modulation Targets mTORC1 Function To Drive Chemokine Receptor-Mediated T Cell Tolerance.
To contain autoimmunity, pathogenic T cells must be eliminated or diverted from reaching the target organ. Recently, we defined a novel form of T cell tolerance whereby treatment with Ag downregulates expression of the chemokine receptor CXCR3 and prevents diabetogenic Th1 cells from reaching the pancreas, leading to suppression of type 1 diabetes (T1D). This report defines the signaling events underlying Ag-induced chemokine receptor-mediated tolerance. Specifically, we show that the mammalian target of rapamycin complex 1 (mTORC1) is a major target for induction of CXCR3 downregulation and crippling of Th1 cells. Indeed, Ag administration induces upregulation of programmed death-ligand 1 on dendritic cells in a T cell-dependent manner. In return, programmed death-ligand 1 interacts with the constitutively expressed programmed death-1 on the target T cells and stimulates docking of Src homology 2 domain-containing tyrosine phosphatase 2 phosphatase to the cytoplasmic tail of programmed death-1. Active Src homology 2 domain-containing tyrosine phosphatase 2 impairs the signaling function of the PI3K/protein kinase B (AKT) pathway, leading to functional defect of mTORC1, downregulation of CXCR3 expression, and suppression of T1D. Thus, mTORC1 component of the metabolic pathway serves as a target for chemokine receptor-mediated T cell tolerance and suppression of T1D.
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212.
Weirong
W
Chen
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212.
Xiaoxiao
X
Wan
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212.
Tobechukwu K
TK
Ukah
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212.
Mindy M
MM
Miller
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212.
Subhasis
S
Barik
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212.
Alexis N
AN
Cattin-Roy
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212; zaghouanih@health.missouri.edu.|Department of Neurology, University of Missouri School of Medicine, Columbia, MO 65212; and.|Department of Child Health, University of Missouri School of Medicine, Columbia, MO 65212.
Habib
0000-0003-4653-0050
H
Zaghouani
D000818:Animals; D000941:Antigens / Q000276:immunology; D015551:Autoimmunity; D060890:B7-H1 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy; D007108:Immune Tolerance; D056747:Immunomodulation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016688:Mice, Inbred NOD; D046912:Multiprotein Complexes / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*
D000941:Antigens; D060890:B7-H1 Antigen; C515188:Cxcr3 protein, mouse; D046912:Multiprotein Complexes; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D054367:Receptors, CXCR3; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
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