Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 4, Pages 1536-1546Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1300438
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Funding
- Commissariat a l'Energie Atomique et aux Energies Alternatives
- Agence de la Biomedecine
- Italian Ministry of Health
- Associazione Italiana per la Ricerca sul Cancro
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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)/G(1) cell cycle arrest through dephosphorylation of AKT, GSK-3 beta, 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.
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