Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors

• Published in: The Journal of clinical investigation 2011-07, Vol.121 (7), p.2614-2624
• Main Authors: Kardava, Lela, Moir, Susan, Wang, Wei, Ho, Jason, Buckner, Clarisa M, Posada, Jacqueline G, O'Shea, Marie A, Roby, Gregg, Chen, Jenny, Sohn, Hae Won, Chun, Tae-Wook, Pierce, Susan K, Fauci, Anthony S
• Format: Article
• Language: English
• Subjects: Antigens, CD - immunology; B cells; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - virology; Biomedical research; Cell death; Cell growth; Cell Proliferation; Cell receptors; Chemokines - immunology; Cytokines - immunology; Health aspects; HIV (Viruses); HIV - immunology; HIV Infections - immunology; Humans; Infections; Kinases; Leukocytes; Ligands; Physiological aspects; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - immunology; RNA; RNA, Small Interfering - genetics; RNA, Small Interfering - immunology; Viral infections
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci45685

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.