title: HLA-G5 induces IL-4 secretion critical for successful pregnancy through differential expression of ILT2 receptor on decidual CD4⁺ T cells and macrophages.
abstract: Successful pregnancy in humans has been associated with production of IL-4 by T cells at the feto-maternal interface. Soluble HLA-G5 produced by trophoblasts potentially controls the decidual T cell cytokine profile. We studied the effect of HLA-G5 on the cytokine profile of purified human macrophages and Ag-specific T cells in vitro. We demonstrated that HLA-G5 increased production of IL-12 by purified peripheral blood macrophages. Although IL-12 production by macrophages is known to induce IFN-γ production by CD4(+) T cells, HLA-G5 increased production of IL-4 but not IFN-γ by CD4(+) T cells after Ag presentation by macrophages. We found that this apparent paradox was due to the differential expression of the ILT2 HLA-G5 receptor on activated T cells and macrophages. This receptor was upregulated in the former and downregulated in the latter after Ag presentation and activation of both cell types. This observation was confirmed in situ, where decidual macrophages and T cells are continuously exposed to HLA-G5 produced locally and activated by trophoblast alloantigens. Freshly isolated decidua basalis macrophages expressed lower levels of ILT2 than peripheral blood macrophages from the same pregnant women. They did not spontaneously produce IL-12, whereas freshly isolated decidual CD4(+) T cells expressed high levels of activation markers (CD25, HLA-DR, and CD69) as well as ILT2 and spontaneously produced IL-4 but not IFN-γ. Therefore, HLA-G5 could be responsible, at least in part, via its interaction with ILT2, for decidual T cell IL-4 production, known to be crucial for successful pregnancy.
authors.affiliation: Department of Experimental and Clinical Medicine, Center of excellence for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to develop novel therapies, University of Florence, 50134 Florence, Italy;
authors.forename: Letizia
authors.initials: L
authors.lastname: Lombardelli
authors.forename: Maryse
authors.initials: M
authors.lastname: Aguerre-Girr
authors.forename: Federica
authors.initials: F
authors.lastname: Logiodice
authors.forename: Ornela
authors.initials: O
authors.lastname: Kullolli
authors.forename: Ysabel
authors.initials: Y
authors.lastname: Casart
authors.forename: Beata
authors.initials: B
authors.lastname: Polgar
authors.forename: Alain
authors.initials: A
authors.lastname: Berrebi
authors.forename: Sergio
authors.initials: S
authors.lastname: Romagnani
authors.forename: Enrico
authors.initials: E
authors.lastname: Maggi
authors.forename: Philippe
authors.initials: P
authors.lastname: Le Bouteiller
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Piccinni
mesh_terms: D000328:Adult; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D059951:HLA-G Antigens / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000378:metabolism*; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D018448:Models, Immunological; D011247:Pregnancy; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D013744:Tetanus Toxin / Q000276:immunology; D014327:Trophoblasts / Q000276:immunology / Q000378:metabolism
chemical_list: D000941:Antigens; D015703:Antigens, CD; D018984:Epitopes, T-Lymphocyte; D059951:HLA-G Antigens; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic; D013744:Tetanus Toxin; D018664:Interleukin-12; D015847:Interleukin-4