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IgE-Mediated Enhancement of CD4(+) T Cell Responses in Mice Requires Antigen Presentation by CD11c(+) Cells and Not by B Cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, e21760- p.Article in journal (Refereed) Published
Abstract [en]

IgE antibodies, administered to mice together with their specific antigen, enhance antibody and CD4(+) T cell responses to this antigen. The effect is dependent on the low affinity receptor for IgE, CD23, and the receptor must be expressed on B cells. In vitro, IgE-antigen complexes are endocytosed via CD23 on B cells, which subsequently present the antigen to CD4(+) T cells. This mechanism has been suggested to explain also IgE-mediated enhancement of immune responses in vivo. We recently found that CD23(+) B cells capture IgE-antigen complexes in peripheral blood and rapidly transport them to B cell follicles in the spleen. This provides an alternative explanation for the requirement for CD23(+) B cells. The aim of the present study was to determine whether B-cell mediated antigen presentation of IgE-antigen complexes explains the enhancing effect of IgE on immune responses in vivo. The ability of spleen cells, taken from mice 1-4 h after immunization with IgE-antigen, to present antigen to specific CD4(+) T cells was analyzed. Antigen presentation was intact when spleens were depleted of CD19(+) cells (i.e., primarily B cells) but was severely impaired after depletion of CD11c(+) cells (i.e., primarily dendritic cells). In agreement with this, the ability of IgE to enhance proliferation of CD4(+) T cells was abolished in CD11c-DTR mice conditionally depleted of CD11c(+) cells. Finally, the lack of IgE-mediated enhancemen of CD4(+) T cell responses in CD23(-/-) mice could be rescued by transfer of MHC-II-compatible as well as by MHC-II-incompatible CD23(+) B cells. These findings argue against the idea that IgE-mediated enhancement of specific CD4(+) T cell responses in vivo is caused by increased antigen presentation by B cells. A model where CD23(+) B cells act as antigen transporting cells, delivering antigen to CD11c(+) cells for presentation to T cells is consistent with available experimental data.

Place, publisher, year, edition, pages
2011. Vol. 6, no 7, e21760- p.
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-156628DOI: 10.1371/journal.pone.0021760ISI: 000292632000024PubMedID: 21765910OAI: oai:DiVA.org:uu-156628DiVA: diva2:432610
Available from: 2011-08-04 Created: 2011-08-04 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Feedback Enhancement of Immune Responses by IgE, IgM, and IgG3 Antibodies
Open this publication in new window or tab >>Feedback Enhancement of Immune Responses by IgE, IgM, and IgG3 Antibodies
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibodies can enhance or suppress the immune responses against their specific antigens. This phenomenon is known as antibody-mediated feedback regulation. We have studied the mechanisms underlying IgE-, IgM-, and IgG3-mediated enhancement of immune responses in mouse models using intravenous immunization. We attempted to answer the following questions: 1) Which cell type presents IgE-complexed antigens to CD4+ T cells? 2) Is complement activation required for specific IgM to enhance antibody responses? 3) Does IgM enhance CD4+ T-cell responses? 4) How are IgG3-antigen complexes transported into B-cell follicles?

We found that CD23+ B cells transporting IgE-antigen complexes into B-cell follicles were not required to prime the antigen-specific CD4+ T cells in vivo, whereas CD11c+ cells were indispensable. After examining the three most common subpopulations of CD11c+ cells in the spleen, we determined that it was CD8α- conventional dendritic cells migrating into the T-cell zone following immunization that presented IgE-complexed antigens to CD4+ T cells.

Next, we showed that specific IgM from Cµ13 mice, which is unable to activate complement, failed to enhance either antibody or germinal center responses whereas wild-type IgM enhanced both responses. Therefore, specific IgM must activate complement to enhance humoral responses. In addition, wild-type IgM did not up-regulate CD4+ T-cell responses.

Finally, we showed that IgG3-antigen complexes were transported by marginal zone B cells into B-cell follicles via binding to complement receptors 1 and 2 (CR1/2) on those cells. The immune complexes were captured by follicular dendritic cells as early as 2 h after immunization. Germinal center responses were also enhanced by IgG3. Using bone marrow chimeric mice, we found that CR1/2 expression was required on both marginal zone B cells and follicular dendritic cells to provide an optimal enhancement of antibody responses.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1061
Keyword
IgE, IgM, IgG3, antibody responses, T-cell responses, antigen transportation, antigen presentation, complement, complement receptors 1 and 2
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-237337 (URN)978-91-554-9129-1 (ISBN)
Public defence
2015-02-12, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2015-01-19 Created: 2014-12-01 Last updated: 2015-03-09Bibliographically approved

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