IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication

• Published in: Journal of leukocyte biology Vol. 87; no. 5; pp. 857 - 867
• Main Authors: Iannello, Alexandre, Boulassel, Mohamed‐Rachid, Samarani, Suzanne, Tremblay, Cécile, Toma, Emil, Routy, Jean‐Pierre, Ahmad, Ali
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.05.2010
• Subjects: Antibody-Dependent Cell Cytotoxicity - immunology; Blotting, Western; CD4-Positive T-Lymphocytes - immunology; Cell Separation; Cells, Cultured; Coculture Techniques; Flow Cytometry; HIV Infections - immunology; HIV-1 - drug effects; HIV-1 - physiology; Humans; Interleukins - immunology; Interleukins - pharmacology; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; LFA‐1; MAPK; perforin; Receptors, Interleukin-21 - biosynthesis; Signal Transduction - drug effects; Signal Transduction - immunology; STAT‐3; Virus Replication - drug effects; Virus Replication - immunology
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.1009701

IL‐21 enhances NK cell functions and survival in healthy and HIV‐infected patients with inhibition of viral replication. IL‐21 plays an important role in regulating immune response and controlling chronic viral infections. Recently, we reported its decreased serum concentrations and their immunological consequences in HIV‐infected persons. In this study, we have investigated how exogenous IL‐21 enhances NK cell responses in these persons. We show that the cytokine receptors are expressed equally on all NK cell subsets defined by expression of CD16 and CD56; the cytokine activates STAT‐3, MAPK, and Akt to enhance NK cell functions; the STAT‐3 activation plays a key role in constitutive and IL‐21‐mediated enhancement of NK cell functions; the cytokine increases expression of antiapoptotic proteins Bcl‐2 and Bcl‐XL and enhances viability of NK cells but has no effect on their proliferation; the cytokine enhances HIV‐specific ADCC, secretory, and cytotoxic functions, as well as viability of NK cells from HIV‐infected persons; it exerts its biological effects on NK cells with minimal stimulation of HIV‐1 replication; and the cytokine‐activated NK cells inhibit viral replication in cocultured, HIV‐infected, autologous CD4+ T cells in a perforin‐ and LFA‐1‐dependent manner. These data suggest that IL‐21 may serve as a valuable therapeutic tool for enhancing NK cell responses and inhibiting viral replication in HIV‐infected patients.