title: Soluble HLA-G inhibits myeloid dendritic cell function in HIV-1 infection by interacting with leukocyte immunoglobulin-like receptor B2.
abstract: Dendritic cells represent a specialized class of professional antigen-presenting cells that are responsible for priming and maintaining antigen-specific effector cell responses and regulating immune activation by cytokine secretion. In HIV-1 infection, myeloid dendritic cells are highly dysfunctional, but mechanisms contributing to their functional alterations are not well defined. Here, we show that soluble molecules of the nonclassical major histocompatibility complex class Ib (MHC-Ib) antigen HLA-G are highly upregulated in the plasma during progressive HIV-1 infection, while levels of membrane-bound HLA-G surface expression on dendritic cells, monocytes, and T cells only slightly differ among HIV-1 progressors, HIV-1 elite controllers, and HIV-1-negative persons. These elevated levels of soluble HLA-G in progressive HIV-1 infection likely result from increased secretion of intracellularly stored HLA-G molecules in monocytes and dendritic cells and contribute to a functional disarray of dendritic cells by inhibiting their antigen-presenting properties, while simultaneously enhancing their secretion of proinflammatory cytokines. Interestingly, we observed that these immunoregulatory effects of soluble HLA-G were mainly mediated by interactions with the myelomonocytic HLA class I receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; ILT4), while binding of soluble HLA-G to its alternative high-affinity receptor, LILRB1 (ILT2), appeared to be less relevant for its immunomodulatory functions on dendritic cells. Overall, these results demonstrate a critical role for soluble HLA-G in modulating the functional characteristics of professional antigen-presenting cells in progressive HIV-1 infection and suggest that soluble HLA-G might represent a possible target for immunotherapeutic interventions in HIV-1-infected persons.
authors: Ragon Institute of MGH, Harvard, MIT, 149, 13th Street, Charlestown, MA 02129, USA.
authors: Jinghe
authors: J
authors: Huang
authors: Patrick
authors: P
authors: Burke
authors: Yue
authors: Y
authors: Yang
authors: Katherine
authors: K
authors: Seiss
authors: Jill
authors: J
authors: Beamon
authors: Thai
authors: T
authors: Cung
authors: Ildiko
authors: I
authors: Toth
authors: Florencia
authors: F
authors: Pereyra
authors: Mathias
authors: M
authors: Lichterfeld
authors: Xu G
authors: XG
authors: Yu
mesh_terms: D000328:Adult; D017951:Antigen Presentation; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D020276:HIV Long-Term Survivors; D015497:HIV-1; D006680:HLA Antigens / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D006680:HLA Antigens; 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; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic