IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation 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-X(L) 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.
Iannello
Alexandre
A
Laboratory of Innate Immunity, CHU-Sainte-Justine Research Center, McGill University, Montreal, Canada.
Boulassel
Mohamed-Rachid
MR
Samarani
Suzanne
S
Tremblay
Cécile
C
Toma
Emil
E
Routy
Jean-Pierre
JP
Ahmad
Ali
A
D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007378:Interleukins / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D053655:Receptors, Interleukin-21 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology*; D000098546:Interleukin-21
D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21