IgG4 drives M2a macrophages to a regulatory M2b‐like phenotype: potential implication in immune tolerance
Open Access
- 18 October 2018
- Vol. 74 (3), 483-494
- https://doi.org/10.1111/all.13635
Abstract
Background Macrophages can be converted in vitro into immunoregulatory M2b macrophages in the presence of immune complexes (ICs), but the role of the specific subclasses IgG1 or IgG4 in this phenotypic and functional change is not known. Objective We aimed to refine the original method by applying precisely defined ICs of the subclasses IgG4 or IgG1 constructed by two independent methods. Methods Monocyte‐derived macrophages (MDMs) were treated with M‐CSF, followed by IL‐4/IL‐13 to induce the M2a allergic phenotype. To mimic unspecific or allergen‐specific ICs, plates were coated with myeloma IgG1 or IgG4, or with grass pollen allergen Phl p 5 followed by recombinant human Phl p 5‐specific IgG1 or IgG4. M2a polarized macrophages were then added, cultured and examined for cellular markers and cytokines by flow cytometry, ELISA, and rtPCR. Alternatively, immune complexes with IgG1 or IgG4 were formed using protein L. Results IgG4 ICs down‐regulated CD163 and CD206 on M2a cells, and significantly increased IL‐10, IL‐6, TNFα and CCL1 secretion, indicating a shift to an M2b‐like phenotype. Treatment with IgG4 ICs resulted in expression of FcγRII and down‐modulation of FcγRII compared to IgG1 treated cells (p= 0.0335) or untreated cells (p < 0.00001). Conclusion Immune complexes with subclasses IgG1 and IgG4 can in vitro be generated by plate absorption, and in fluid form by protein L. Crosslinking of FcγRIIb by the IgG4 subclass redirects pro‐allergic M2a macrophages to an M2b‐like immunosuppressive phenotype. This suggests an interplay of macrophages with IgG4 in immune tolerance, likely relevant in allergen immunotherapy.Keywords
Funding Information
- Austrian Science Fund (SFB F4606-B28)
This publication has 39 references indexed in Scilit:
- AllergoOncology: IgE- and IgG 4 -mediated immune mechanisms linking allergy with cancer and their translational implicationsJournal of Allergy and Clinical Immunology, 2017
- Understanding the Mysterious M2 Macrophage through Activation Markers and Effector MechanismsMediators of Inflammation, 2015
- IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic AsthmaPublished by The American Association of Immunologists ,2015
- IgG4 can induce an M2-like phenotype in human monocyte-derived macrophages through FcγRImAbs, 2014
- The function of Fcγ receptors in dendritic cells and macrophagesNature Reviews Immunology, 2014
- CCL1 released from M2b macrophages is essentially required for the maintenance of their propertiesJournal of Leukocyte Biology, 2012
- Recombinant monoclonal human immunoglobulin E to investigate the allergenic activity of major grass pollen allergen Phl p 5Clinical and Experimental Allergy, 2010
- Immunoglobulin Superantigen Protein L Induces IL-4 and IL-13 Secretion from Human FcεRI+ Cells Through Interaction with the κ Light Chains of IgEPublished by The American Association of Immunologists ,2003
- Alternative activation of macrophagesNature Reviews Immunology, 2003
- A Human Monoclonal IgE Antibody Defines a Highly Allergenic Fragment of the Major Timothy Grass Pollen Allergen, Phl p 5: Molecular, Immunological, and Structural Characterization of the Epitope-Containing DomainThe Journal of Immunology, 2000