Multimeric structures of HLA-G isoforms function through differential binding to LILRB receptors.
The non-classical Human leukocyte antigen G (HLA-G) differs from classical HLA class I molecules by its low genetic diversity, a tissue-restricted expression, the existence of seven isoforms, and immuno-inhibitory functions. Most of the known functions of HLA-G concern the membrane-bound HLA-G1 and soluble HLA-G5 isoforms, which present the typical structure of classical HLA class I molecule: a heavy chain of three globular domains α1-α2-α3 non-covalently bound to β-2-microglobulin (B2M) and a peptide. Very little is known of the structural features and functions of other HLA-G isoforms or structural conformations other than B2M-associated HLA-G1 and HLA-G5. In the present work, we studied the capability of all isoforms to form homomultimers, and investigated whether they could bind to, and function through, the known HLA-G receptors LILRB1 and LILRB2. We report that all HLA-G isoforms may form homodimers, demonstrating for the first time the existence of HLA-G4 dimers. We also report that the HLA-G α1-α3 structure, which constitutes the extracellular part of HLA-G2 and HLA-G6, binds the LILRB2 receptor but not LILRB1. This is the first report of a receptor for a truncated HLA-G isoform. Following up on this finding, we show that the α1-α3-Fc structure coated on agarose beads is tolerogenic and capable of prolonging the survival of skin allografts in B6-mice and in a LILRB2-transgenic mouse model. This study is the first proof of concept that truncated HLA-G isoforms could be used as therapeutic agents.
CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475, Paris, France.
Kiave-Yune
KY
HoWangYin
Maria
M
Loustau
Juan
J
Wu
Estibaliz
E
Alegre
Marina
M
Daouya
Julien
J
Caumartin
Sylvie
S
Sousa
Anatolij
A
Horuzsko
Edgardo D
ED
Carosella
Joel
J
LeMaoult
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001667:Binding, Competitive; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006085:Graft Survival; D057809:HEK293 Cells; D059951:HLA-G Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D016038:Skin Transplantation; D014184:Transplantation, Homologous; D001613:beta 2-Microglobulin / Q000378:metabolism
D015703:Antigens, CD; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; C105299:LILRB1 protein, human; C491341:LILRB2 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011971:Receptors, Immunologic; D001613:beta 2-Microglobulin