Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells.
Mature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T cell tolerance. Using various genetic approaches, we depleted CD11c(+) DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice. Furthermore, when we engineered DCs to present a CNS-associated autoantigen in an induced manner, we found robust tolerance that prevented disease, which coincided with an upregulation of the PD-1 receptor on antigen-specific T cells. Additionally, we showed that PD-1 was necessary for DC-mediated induction of regulatory T cells. Our results show that a reduction of DCs interferes with tolerance, resulting in a stronger inflammatory response, and that other APC populations could compensate for the loss of immunogenic APC function in DC-depleted mice.
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany. yogev@uni-mainz.de
Nir
N
Yogev
Friederike
F
Frommer
Dominika
D
Lukas
Kordula
K
Kautz-Neu
Khalad
K
Karram
Daniele
D
Ielo
Esther
E
von Stebut
Hans-Christian
HC
Probst
Maries
M
van den Broek
Dieter
D
Riethmacher
Tal
T
Birnberg
Thomas
T
Blank
Boris
B
Reizis
Thomas
T
Korn
Heinz
H
Wiendl
Steffen
S
Jung
Marco
M
Prinz
Florian C
FC
Kurschus
Ari
A
Waisman
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D039521:CD11c Antigen; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism
D001324:Autoantigens; D060890:B7-H1 Antigen; D039521:CD11c Antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor