Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses

Abderrahim Naji, Catherine Menier, Fabio Morandi, Sophie Agaugué, Guitta Maki, Elisa Ferretti, Sylvie Bruel, Vito Pistoia, Edgardo D. Carosella, Nathalie Rouas-Freiss

Research output: Contribution to journalArticle

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Abstract

Inhibition of B cells constitutes a rational approach for treating B cell-mediated disorders. We demonstrate in this article that the engagement of the surface Ig-like transcript 2 (ILT2) inhibitory receptor with its preferential ligand HLA-G is critical to inhibit B cell functions. Indeed, ILT2-HLA-G interaction impedes both naive and memory B cell functions in vitro and in vivo. Particularly, HLA-G inhibits B cell proliferation, differentiation, and Ig secretion in both T cell-dependent and -independent models of B cell activation. HLA-G mediates phenotypic and functional downregulation of CXCR4 and CXCR5 chemokine receptors on germinal center B cells. In-depth analysis of the molecular mechanisms mediated by ILT2-HLA-G interaction showed a G 0/G1 cell cycle arrest through dephosphorylation of AKT, GSK-3β, c-Raf, and Foxo proteins. Crucially, we provide in vivo evidence that HLA-G acts as a negative B cell regulator in modulating B cell Ab secretion in a xenograft mouse model. This B cell regulatory mechanism involving ILT2-HLA-G interaction brings important insight to design future B cell-targeted therapies aimed at reducing inappropriate immune reaction in allotransplantation and autoimmune diseases.

Original languageEnglish
Pages (from-to)1536-1546
Number of pages11
JournalJournal of Immunology
Volume192
Issue number4
DOIs
Publication statusPublished - Feb 15 2014

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HLA-G Antigens
B-Lymphocytes
CXCR5 Receptors
Regulatory B-Lymphocytes
Proto-Oncogene Proteins c-raf
G1 Phase Cell Cycle Checkpoints
Glycogen Synthase Kinase 3
Germinal Center
Chemokine Receptors
Cell- and Tissue-Based Therapy
Heterografts
Autoimmune Diseases
Cell Differentiation
Down-Regulation
Cell Proliferation

ASJC Scopus subject areas

  • Immunology

Cite this

Naji, A., Menier, C., Morandi, F., Agaugué, S., Maki, G., Ferretti, E., ... Rouas-Freiss, N. (2014). Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses. Journal of Immunology, 192(4), 1536-1546. https://doi.org/10.4049/jimmunol.1300438

Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses. / Naji, Abderrahim; Menier, Catherine; Morandi, Fabio; Agaugué, Sophie; Maki, Guitta; Ferretti, Elisa; Bruel, Sylvie; Pistoia, Vito; Carosella, Edgardo D.; Rouas-Freiss, Nathalie.

In: Journal of Immunology, Vol. 192, No. 4, 15.02.2014, p. 1536-1546.

Research output: Contribution to journalArticle

Naji, A, Menier, C, Morandi, F, Agaugué, S, Maki, G, Ferretti, E, Bruel, S, Pistoia, V, Carosella, ED & Rouas-Freiss, N 2014, 'Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses', Journal of Immunology, vol. 192, no. 4, pp. 1536-1546. https://doi.org/10.4049/jimmunol.1300438
Naji, Abderrahim ; Menier, Catherine ; Morandi, Fabio ; Agaugué, Sophie ; Maki, Guitta ; Ferretti, Elisa ; Bruel, Sylvie ; Pistoia, Vito ; Carosella, Edgardo D. ; Rouas-Freiss, Nathalie. / Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses. In: Journal of Immunology. 2014 ; Vol. 192, No. 4. pp. 1536-1546.
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