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

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

ASJC Scopus subject areas

  • Immunology

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    Naji, A., Menier, C., Morandi, F., Agaugué, S., Maki, G., Ferretti, E., Bruel, S., Pistoia, V., Carosella, E. D., & 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