title: Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors.
abstract: Chronic immune activation in HIV-infected individuals leads to accumulation of exhausted tissue-like memory B cells. Exhausted lymphocytes display increased expression of multiple inhibitory receptors, which may contribute to the inefficiency of HIV-specific antibody responses. Here, we show that downregulation of B cell inhibitory receptors in primary human B cells led to increased tissue-like memory B cell proliferation and responsiveness against HIV. In human B cells, siRNA knockdown of 9 known and putative B cell inhibitory receptors led to enhanced B cell receptor-mediated (BCR-mediated) proliferation of tissue-like memory but not other B cell subpopulations. The strongest effects were observed with the putative inhibitory receptors Fc receptor-like-4 (FCRL4) and sialic acid-binding Ig-like lectin 6 (Siglec-6). Inhibitory receptor downregulation also led to increased levels of HIV-specific antibody-secreting cells and B cell-associated chemokines and cytokines. The absence of known ligands for FCRL4 and Siglec-6 suggests these receptors may regulate BCR signaling through their own constitutive or tonic signaling. Furthermore, the extent of FCLR4 knockdown effects on BCR-mediated proliferation varied depending on the costimulatory ligand, suggesting that inhibitory receptors may engage specific pathways in inhibiting B cell proliferation. These findings on HIV-associated B cell exhaustion define potential targets for reversing the deleterious effect of inhibitory receptors on immune responses against persistent viral infections.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892-1576, USA.
authors.forename: Lela
authors.initials: L
authors.lastname: Kardava
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jason
authors.initials: J
authors.lastname: Ho
authors.forename: Clarisa M
authors.initials: CM
authors.lastname: Buckner
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: Posada
authors.forename: Marie A
authors.initials: MA
authors.lastname: O'Shea
authors.forename: Gregg
authors.initials: G
authors.lastname: Roby
authors.forename: Jenny
authors.initials: J
authors.lastname: Chen
authors.forename: Hae Won
authors.initials: HW
authors.lastname: Sohn
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chun
authors.forename: Susan K
authors.initials: SK
authors.lastname: Pierce
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D049109:Cell Proliferation; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D018925:Chemokines; D016207:Cytokines; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell