Specialized role of migratory dendritic cells in peripheral tolerance induction
Juliana Idoyaga, Christopher Fiorese, Lori Zbytnuik, Ashira Lubkin, Jennifer Miller, Bernard Malissen, Daniel Mucida, Miriam Merad, Ralph M. Steinman
Juliana Idoyaga, Christopher Fiorese, Lori Zbytnuik, Ashira Lubkin, Jennifer Miller, Bernard Malissen, Daniel Mucida, Miriam Merad, Ralph M. Steinman
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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 7

α-Langerin– and α-DEC–generated Foxp3+ T cells are functional Tregs that prevent the development and progression of EAE.

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α-Langerin– and α-DEC–generated Foxp3+ T cells are functional Tregs that...
(A) One day after transfer of 4 × 106 MOG-specific CD4+ T cells (day –15), B6 mice were inoculated s.c. with 3 μg α-receptor mAbs (day –14). EAE was induced on day 0, and disease was monitored for 40 days. Mean clinical score ± SEM is plotted over time (10–20 mice in 2–4 experiments). α-DEC and α-Langerin mAbs were statistically significant (2-way ANOVA and Bonferroni’s post hoc testing) from control Ig, α-DCIR2, and α-Treml4 mAbs (starting on day 17, *P < 0.05). Further information can be found in Supplemental Table 1. (B) Recipient B6 mice transferred with 8 × 106 MOG-specific Foxp3-DTR CD4+ T cells (day –15) 1 day before s.c. inoculation of 3 μg α-Langerin–MOGp (day –14) were inoculated i.v. (day –2) and i.p. (day 1) with 250 ng DT. FACS plots (representative of 3 experiments) show depletion of MOG-specific Foxp3+ T cells in sLN 1 day after the last DT inoculation. (C) As in B, but on day 0 mice were challenged for EAE induction. Data are shown as the mean clinical score ± SEM of 15–20 mice per group in 3–4 experiments. The α-Langerin–MOGp –DT group was statistically significant (2-way ANOVA and Bonferroni’s post hoc testing) from the α-Langerin–MOGp +DT and the control Ig-MOGp groups (starting on day 21, *P < 0.05).