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.
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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

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Figure 2

Targeting MOGp to DEC+ and Langerin+ DCs expands and induces de novo Foxp3+ T cells in vivo.

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Targeting MOGp to DEC+ and Langerin+ DCs expands and induces de novo Fox...
(A) Experimental design (left) to assess the proliferation of MOG-specific CD4+ T cell in sLN 4 days after s.c. inoculation of α-receptor–MOGp mAbs. Histograms (right) are gated on MOG-specific donor T cells (Vβ11+, CD45.1+), and are representative of 2–3 experiments. (B) De novo induction of Foxp3+ T cells by α-receptor–MOGp mAbs. 4 × 106 naive CD4+ T cells (CD25–, Foxp3-EGFP–, CD44lo, CD45RBhi) FACS sorted from MOG-specific Foxp3-EGFP reporter mice (see Supplemental Figure 3A for sorting strategy) were transferred 1 day before the inoculation of 3 μg α-receptor–MOGp mAbs s.c. footpad. Seven days later, the frequency (left) and total number (right) of induced MOG-specific Foxp3-EGFP+ T cells were analyzed in the sLN or spleen. Bars are the mean ± SEM of 4–8 mice in 2–4 experiments. (C) Expansion of nTregs by α-receptor–MOGp mAbs. Recipient mice were co-transferred with 1 × 106 Violet-labeled MOG-specific CD45.1 Foxp3-EGFP+ nTregs and 4 × 106 MOG-specific CD45.2 naive T cells (left panels show sorting strategy) 1 day before inoculation of 3 μg α-receptor–MOGp mAbs s.c. via footpad. Histograms (right) show the proliferation of Violet-labeled MOG-specific Foxp3+ nTregs in spleen and sLN and are representative of 2 experiments.