Immunomodulation

Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR-L interaction, IL-10 and TGF-β

  1. Judith S. Satoguina1,2,†,
  2. Tomabu Adjobimey1,†,
  3. Kathrin Arndts1,
  4. Jochen Hoch3,
  5. Johannes Oldenburg3,
  6. Laura E. Layland1,†,
  7. Achim Hoerauf1,†,*

Article first published online: 16 OCT 2008

DOI: 10.1002/eji.200838193

Issue

European Journal of Immunology

European Journal of Immunology

Volume 38, Issue 11, pages 3101–3113, November 2008

Additional Information

How to Cite

Satoguina, J. S., Adjobimey, T., Arndts, K., Hoch, J., Oldenburg, J., Layland, L. E. and Hoerauf, A. (2008), Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR-L interaction, IL-10 and TGF-β. Eur. J. Immunol., 38: 3101–3113. doi: 10.1002/eji.200838193

Author Information

  1. 1

    Institute of Medical Microbiology, Immunology and Parasitology, University Clinic Bonn, Bonn, Germany

  2. 2

    Malaria Unit, Medical Research Council, The Gambia

  3. 3

    Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany

  1. †

    These authors contributed equally to this work.

*Institute of Medical Microbiology, Immunology and Parasitology, University Clinic Bonn, Sigmund Freud Straße 25, 53105 Bonn, Germany Fax: +49-228-28719573

Publication History

  1. Issue published online: 7 NOV 2008
  2. Article first published online: 16 OCT 2008
  3. Manuscript Accepted: 13 AUG 2008
  4. Manuscript Revised: 20 JUN 2008
  5. Manuscript Received: 25 JAN 2008

Funded by

  • German Research Council. Grant Number: DFG, HO2009/8-1
  • North Rhine Westfalian Ministry of Research
  • German Academic Exchange Service (DAAD)

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Keywords:

  • Dexamethasone and cytokines;
  • GITR;
  • Human Treg;
  • IgG4

Abstract

Regulatory T cells exert their function through the modulation of both T and B cell responses. Our previous studies demonstrated that IL-10-producing Treg (Tr1) can induce B cells to secrete IgG4 in a cell-contact-dependent manner. The benefit of such non-inflammatory B-cell responses is apparent in the hyporesponsive state of patients with helminth infections such as Onchocerciasis. Here, we investigated the mechanisms involved to induce IgG4, within B:Tr-cell co-cultures, using IL-10-producing tetanus-toxoid-specific regulatory T cell lines and clones (Tr-TCC) from human PBMC. During the generation process, we found that increasing Foxp3 levels in regulatory T cell lines correlated with their ability to induce IgG4 in B cells. Using Tr-TCC, we found that blocking glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) molecules selectively prevented IgG4 production as did neutralizing Ab to glucocorticoid-induced tumour necrosis factor receptor-related protein ligand (GITR-L), IL-10 and TGF-β. Furthermore, the prevention of IgG4 induction by anti-GITR Ab was reversed by excess rIL-10 but not rTGF-β. In contrast, anti-ICOS and anti-CTLA-4 Abs had no effect. When compared with Tr-TCC, freshly isolated CD4+CD25+ T cells, but not effector T cell populations, induced low levels of IgG4, which were also blocked by anti-GITR and anti-GITR-L Ab. Thus, the mechanism of IgG4 induction by regulatory cells involves GITR–GITR-L interactions, IL-10 and TGF-β.

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