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Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes

Nature Medicine volume 20, pages 1458–1463 (2014)Cite this article

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Abstract

Antibodies are critical for defense against a variety of microbes, but they may also be pathogenic in some autoimmune diseases. Many effector functions of antibodies are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs)—important antigen-presenting cells that play a central role in inducing antigen-specific tolerance or immunity1,2. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via the lymphatics to present antigen to T cells. Here we demonstrate that FcγR engagement by IgG immune complexes (ICs) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated mouse and human DCs showed greater directional migration in a chemokine (C-C) ligand 19 (CCL19) gradient and increased chemokine (C-C) receptor 7 (CCR7) expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilization. We confirmed that dermal DC migration to lymph nodes depended on CCR7 and increased in the absence of the inhibitory receptor FcγRIIB. These observations have relevance to autoimmunity because autoantibody-containing serum from humans with systemic lupus erythematosus (SLE) and from a mouse model of SLE also increased dermal DC migration in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localization of autoantigen-bearing DCs.

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Figure 1: ICs increase CCR7 expression, matrix metalloprotease production and migration of mouse bone marrow–derived DCs.
Figure 2: IC FcγR engagement promotes chemokine-directed mouse and human DC migration in vitro.
Figure 3: ICs stimulate CCR7-dependent dermal DC migration to lymph nodes in vivo.
Figure 4: Sera from NZB/W SLE model mice and from humans with lupus stimulate dermal DC migration to lymph nodes in vivo.

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Acknowledgements

This work was supported by a Wellcome Trust Intermediate Fellowship (WT081020) to M.R.C. and by the National Institute for Health Research Cambridge Biomedical Research Centre and the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, part of the US National Institutes of Health. We thank J. Yoon for technical advice and M. Espeli for helpful discussions.

Author information

Authors and Affiliations

  1. Department of Medicine, MRC Laboratory of Molecular Biology, University of Cambridge, Cambridge, UK

    Menna R Clatworthy & Rebeccah J Mathews

  2. Laboratory of Systems Biology, Lymphocyte Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Menna R Clatworthy, Caren E Petrie Aronin & Ronald N Germain

  3. Biomedical Engineering and Physical Sciences Resource, Microfabrication and Microfluidics Unit, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA

    Nicole Y Morgan

  4. Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK

    Kenneth G C Smith

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Contributions

M.R.C. conceived of the project, carried out experiments, designed and supervised experiments, analyzed data and wrote the manuscript. C.E.P.A. and R.J.M. carried out experiments and analyzed data. N.Y.M. provided technical advice to C.E.P.A. for the in vitro DC chemotaxis assay. K.G.C.S. provided mentorship for M.R.C. and scientific advice. R.N.G. provided advice on experimental design, assisted with manuscript writing and editing and provided mentorship for M.R.C. and C.E.P.A.

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Correspondence to Menna R Clatworthy or Ronald N Germain.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–14 and Supplementary Table 1 (PDF 2077 kb)

Migration of WT BMDCs from the skin through the interfollicular zone of the draining lymph node.

Representative movie of WT BMDC migration (green) in vivo in the popliteal lymph node, 20 hours following their administration subcutaneously into the footpad. Lymph node imaged over 1 hour and DCs are observed moving deeper into the lymph node paracortex. (MOV 310 kb)

Chemotaxis of OVA-stimulated WT DCs in a CCL19 gradient in vitro

Representative movie of cell migration observed for WT BMDCs (green) placed in a soluble rising CCL19 gradient following 24 hour incubation with ovalbumin prior to transfer into a 3D collagen matrix. The CCL19 gradient develops from left (source concentration) to right (base medium). Cell tracks (multi-color) demonstrate migration paths taken by motile cells exposed to soluble gradient over 1 hour. (MOV 436 kb)

Chemotaxis of immune complex-stimulated WT DCs in a CCL19 gradient in vitro

Representative movie of cell migration observed for WT BMDCs (green) placed in a soluble rising CCL19 gradient following 24 hour incubation with IgG-opsonised ovalbumin prior to transfer into a 3D collagen matrix. The CCL19 gradient develops from left (source concentration) to right (base medium). Cell tracks (multi-color) demonstrate migration paths taken by motile cells exposed to soluble gradient over 1 hour. (MOV 773 kb)

Chemotaxis of OVA-stimulated Fcgr2b–/– DCs in a CCL19 gradient in vitro

Representative movie of cell migration observed for Fcgr2b–/– BMDCs (green) placed in a soluble rising CCL19 gradient following 24 hour incubation with ovalbumin prior to transfer into a 3D collagen matrix. The CCL19 gradient develops from left (source concentration) to right (base medium). Cell tracks (multi-color) demonstrate migration paths taken by motile cells exposed to soluble gradient over 1 hour. (MOV 992 kb)

Chemotaxis of immune complex-stimulated Fcgr2b–/– DCs in a CCL19 gradient in vitro

Representative movie of cell migration observed for Fcgr2b–/– BMDCs (green) placed in a soluble rising CCL19 gradient following 24 hour incubation with IgG-opsonised ovalbumin prior to transfer into a 3D collagen matrix. The CCL19 gradient develops from left (source concentration) to right (base medium). Cell tracks (multi-color) demonstrate migration paths taken by motile cells exposed to soluble gradient over 1 hour. (MOV 1210 kb)

Chemotaxis of OVA-stimulated human monocyte-derived DCs in a CCL19 gradient in vitro

Representative movie of cell migration observed for human monocyte-derived DCs placed in a soluble rising CCL19 gradient following 24 hour incubation with ovalbumin prior to transfer into a 3D collagen matrix. The CCL19 gradient develops from left (source concentration) to right (base medium). Cell tracks (multi-color) demonstrate migration paths taken by motile cells exposed to soluble gradient over 1 hour. (MOV 9849 kb)

Chemotaxis of immune complex-stimulated human monocyte-derived DCs in a CCL19 gradient in vitro

Representative movie of cell migration observed for human monocyte-derived DCs placed in a soluble rising CCL19 gradient following 24 hour incubation with IgG-opsonised ovalbumin prior to transfer into a 3D collagen matrix. The CCL19 gradient runs from left (source concentration) to right (base medium). Cell tracks (multi-color) demonstrate migration paths taken by motile cells exposed to soluble gradient over 1 hour. (MOV 9310 kb)

Footpad dermal DC migration following administration of ovalbumin

Representative movie of endogenous dermal DC migration in WT CD11cEYFP mice 16 hours following the administration (footpad injection) of ovalbumin. Individual movies of dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Blood vessels delineated with 655 Qdot tracer (red). (MP4 2412 kb)

Footpad dermal DC migration following administration of immune complexes

Representative movie of endogenous dermal DC migration in WT CD11cEYFP mice 16 hours following the administration (footpad injection) of IgG-opsonised ovalbumin. Individual movies of dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Blood vessels delineated with a 655 Qdot tracer (red). (MP4 1966 kb)

Footpad dermal DC migration into lymphatics following administration of immune complexes

Right, representative movie of endogenous dermal DC migration in WT CD11cEYFP mice 16 hours following the administration (footpad injection) of IgG-opsonised ovalbumin. Dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Lymphatic vessels delineated with an anti-LYVE-1 antibody (red) administered intra-dermally. Left, movie rotated and viewed in perpendicular plane to that viewed at right; confirms that the DC is moving within the lymphatic vessel rather than adjacent to it. (MOV 1360 kb)

Footpad dermal DC migration in Fcgr2b–/– mice following administration of ovalbumin

Representative movie of endogenous dermal DC migration in Fcgr2b–/– CD11cEYFP mice 16 hours following the administration (footpad injection) of ovalbumin. Individual movies of dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Blood vessels delineated with a 655 Qdot tracer (red). (MOV 1783 kb)

Footpad dermal DC migration in Fcgr2b–/– mice following administration of immune complexes

Representative movie of endogenous dermal DC migration in Fcgr2b–/– CD11cEYFP mice 16 hours following the administration (footpad injection) of IgG-opsonised ovalbumin. Individual movies of dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Blood vessels delineated with a 655 Qdot tracer (red). (MOV 1774 kb)

Footpad dermal DC migration following administration of heat-inactivated serum from an NZB/W F1 mouse

Representative movie of endogenous dermal DC migration in WT CD11cEYFP mice 16 hours following the administration (footpad injection) of heat-inactivated serum obtained from an NZB/W F1 mouse with anti-nuclear antibodies and nephritis. Individual movies of dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Blood vessels delineated with a 655 Qdot tracer (red). (MOV 1448 kb)

Footpad dermal DC migration following administration of heat-inactivated serum from an aged WT mouse

Representative movie of endogenous dermal DC migration in WT CD11cEYFP mice 16 hours following the administration (footpad injection) of heat-inactivated serum obtained from an aged WT mouse. Individual movies of dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Blood vessels delineated with a 655 Qdot tracer (red). (MOV 1509 kb)

Footpad dermal DC migration following administration of heat-inactivated serum from a patient with SLE

Representative movie of endogenous dermal DC migration in WT CD11cEYFP mice 16 hours following the administration (footpad injection) of heat-inactivated serum obtained from a patient with systemic lupus erythematosus. Individual movies of dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Blood vessels delineated with a 655 Qdot tracer (red). (MOV 1167 kb)

Footpad dermal DC migration following administration of heat-inactivated serum from a healthy control

Representative movie of endogenous dermal DC migration in WT CD11cEYFP mice 16 hours following the administration (footpad injection) of heat-inactivated serum obtained from a healthy control subject. Individual movies of dermal DCs (green) imaged over 1.5 hours with migration tracks shown in white. Blood vessels delineated with a 655 Qdot tracer (red). (MOV 1657 kb)

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Clatworthy, M., Aronin, C., Mathews, R. et al. Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes. Nat Med 20, 1458–1463 (2014). https://doi.org/10.1038/nm.3709

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