Specialized role of migratory dendritic cells in peripheral tolerance induction
Juliana Idoyaga, … , Miriam Merad, Ralph M. Steinman
Juliana Idoyaga, … , Miriam Merad, Ralph M. Steinman
Published January 9, 2013
Citation Information: J Clin Invest. 2013;123(2):844-854. https://doi.org/10.1172/JCI65260.
View: Text | PDF
Research Article Immunology

Specialized role of migratory dendritic cells in peripheral tolerance induction

Abstract

Harnessing DCs for immunotherapies in vivo requires the elucidation of the physiological role of distinct DC populations. Migratory DCs traffic from peripheral tissues to draining lymph nodes charged with tissue self antigens. We hypothesized that these DC populations have a specialized role in the maintenance of peripheral tolerance, specifically, to generate suppressive Foxp3+ Tregs. To examine the differential capacity of migratory DCs versus blood-derived lymphoid-resident DCs for Treg generation in vivo, we targeted a self antigen, myelin oligodendrocyte glycoprotein, using antibodies against cell surface receptors differentially expressed in these DC populations. Using this approach together with mouse models that lack specific DC populations, we found that migratory DCs have a superior ability to generate Tregs in vivo, which in turn drastically improve the outcome of experimental autoimmune encephalomyelitis. These results provide a rationale for the development of novel therapies targeting migratory DCs for the treatment of autoimmune diseases.

Authors

Juliana Idoyaga, Christopher Fiorese, Lori Zbytnuik, Ashira Lubkin, Jennifer Miller, Bernard Malissen, Daniel Mucida, Miriam Merad, Ralph M. Steinman

×

Figure 4

Skin Langerin+ migratory DCs mediate Foxp3+ T cell generation after α-DEC and α-Langerin targeting.

Options: View larger image (or click on image) Download as PowerPoint
Skin Langerin+ migratory DCs mediate Foxp3+ T cell generation after α-DE...
(A) Generation of MOG-specific Foxp3+ T cells in sLN of B6 WT, sham, or splenectomized (Splenec) mice. Mice receiving transfer of 4 × 106 MOG-specific CD4+ T cells 1 day before s.c. inoculation of 3 μg α-Langerin– or α-DEC–MOGp were analyzed 7 days later. Mean ± SEM of 2 experiments with 4 mice per group. (B) As in A, but comparing MOG-specific Foxp3+ T cell generation in sLN and spleen of B6 WT and Ccr7–/– mice. Mice inoculated with untargeted MOG35-55p received 300 μg. Mean ± SEM of 4–8 mice in 2–4 experiments. (C) Four-day proliferation of Violet-labeled MOG-specific CD45.1+CD4+ T cells (4 × 106) transferred into CD45.2 WT or Ccr7–/– recipient mice 1 day before s.c. inoculation of untargeted MOG35-55p (300 μg). Gates represent the percentage of donor CD45.1+ T cells undergoing one or more divisions. Plots are gated on CD3ε+CD4+ T cells and are representative of 2 experiments. (D) Generation of MOG-specific Foxp3+ T cells in sLN of mice depleted of Langerin+ cells. As in B, but Langerin-DTR mice were treated with or without 500 ng DT i.v. the day of T cell transfer (day –1), followed by 250 ng DT i.p. on days 1, 3, and 5. Mean ± SEM of 4–6 mice per group in 2–3 experiments.