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 1

α-DEC and α-Langerin, but not α-DCIR2 and α-Treml4 mAbs, target skin migratory DCs in vivo.

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α-DEC and α-Langerin, but not α-DCIR2 and α-Treml4 mAbs, target skin mig...
(A) Gating strategy for DC subsets in sLN (see also Supplemental Figure 1). Live lineage– cells (CD19–Ter119–DX5–CD3ε–) were examined for CD11c and MHC II (center panel). CD11chiMHC IIint DCs were stained for the expression of CD8 to identify CD8+ (i) and CD8– (ii) DC subsets (left panel). ~25% of CD8+ DCs in B6 mice expressed Langerin (overlaid red dot plot). CD11cint/hi MHC IIhi migratory DCs were further gated into CD11bhi DCs (iii), CD11b– DCs (iv), Langerin+CD103+ DCs (v), and Langerin+ CD103– LCs (vi). (B) Microarray analysis of Ly75 (DEC), Clec4a4 (DCIR2), Cd207 (Langerin), and Treml4 by distinct migratory and lymphoid-resident DC subsets sorted from spleen or sLN. Lymphoid-resident DCs were sorted based on CD8 and CD4 expression. Heat map depicts normalized values averaged from 3 replicates. Red and blue represent high and low relative expression, respectively. (C) Protein expression of DEC, DCIR2, and Treml4 by distinct DC subsets analyzed by FACS. (D) Langerin-EGFP mice were inoculated s.c. via footpad with 10 μg Alexa Fluor 647–labeled α-receptor mAbs or control Ig mAb (GL117, gray histograms). Uptake of labeled mAb by distinct DC populations in the spleen and sLN was evaluated 18–24 hours later by FACS. One experiment representative of 2–3 is shown.