Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses.
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 G0/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.
Commissariat à l'Energie Atomique et aux Énergies Alternatives, Institut des Maladies Emergentes et des Therapies Innovantes, Service de Recherche en Hemato-Immunologie, Hopital Saint-Louis, 75010 Paris, France;
Abderrahim
A
Naji
Catherine
C
Menier
Fabio
F
Morandi
Sophie
S
Agaugué
Guitta
G
Maki
Elisa
E
Ferretti
Sylvie
S
Bruel
Vito
V
Pistoia
Edgardo D
ED
Carosella
Nathalie
N
Rouas-Freiss
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000276:immunology; D018858:Germinal Center / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D059951:HLA-G Antigens / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D014066:Palatine Tonsil / Q000276:immunology; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D054380:Receptors, CXCR5 / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014183:Transplantation, Heterologous
D015703:Antigens, CD; C514936:CXCR4 protein, mouse; C513179:CXCR5 protein, mouse; D051858:Forkhead Transcription Factors; D059951:HLA-G Antigens; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D019718:Receptors, CXCR4; D054380:Receptors, CXCR5; D011971:Receptors, Immunologic; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D038362:Glycogen Synthase Kinase 3