Transient systemic inflammation does not alter the induction of tolerance to gastric autoantigens by migratory dendritic cells.
It has been proposed that activation of dendritic cells (DCs) presenting self-antigens during inflammation may lead to activation of autoreactive T cells and the development of autoimmunity. To test this hypothesis, we examined the presentation of the autoantigen recognized in autoimmune gastritis, gastric H(+)/K(+) ATPase, which is naturally expressed in the stomach and is constitutively presented in the stomach-draining lymph nodes. Systemic administration to mice of the TLR9 agonist CpG DNA, agonist anti-CD40 Ab, or TLR4 agonist LPS all failed to abrogate the process of peripheral clonal deletion of H(+)/K(+) ATPase-specific CD4 T cells or promote the development of autoimmune gastritis. We demonstrated that migratory DCs from the stomach-draining lymph nodes are the only DC subset capable of constitutively presenting the endogenous gastric H(+)/K(+) ATPase autoantigen in its normal physiological context. Analysis of costimulatory molecules indicated that, relative to resident DCs, migratory DCs displayed a partially activated phenotype in the steady state. Furthermore, migratory DCs were refractory to stimulation by transient exposure to TLR agonists, as they failed to upregulate costimulatory molecules, secrete significant amounts of inflammatory cytokines, or induce differentiation of effector T cells. Together, these data show that transient systemic inflammation failed to break tolerance to the gastric autoantigen, as migratory DCs presenting the gastric autoantigen remain tolerogenic under such conditions, demonstrating the robust nature of peripheral tolerance.
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia; dbourges@unimelb.edu.au i.vandriel@unimelb.edu.au.
Dorothée
D
Bourges
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
Ellen M
EM
Ross
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
Stacey
S
Allen
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
Simon
S
Read
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
Fiona J
FJ
Houghton
Department of Microbiology and Immunology, Peter Doherty Institute for Immunology and Infection, The University of Melbourne, Parkville, Victoria 3010, Australia; and.
Sammy
S
Bedoui
Bioceros Holding BV, 3584 CM Utrecht, The Netherlands.
Louis
L
Boon
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia;
Paul A
PA
Gleeson
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia; dbourges@unimelb.edu.au i.vandriel@unimelb.edu.au.
Ian R
IR
van Driel
D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000009:adverse effects / Q000494:pharmacology; D013270:Stomach / Q000276:immunology* / Q000473:pathology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D001324:Autoantigens; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9