Interleukin-21 (IL-21) is produced primarily by CD4+ T cells and regulates immunity against human/simian immunodeficiency virus (HIV/SIV) infection. Activated CD8+ cells and their secreted interferon-gamma (IFN-γ) are crucial for the control of acute HIV/SIV infection. However, whether IL-21 can regulate IFN-γ production by CD8+ cells remains controversial. Rhesus macaques (RMs, n = 8) were infected with SHIV and the levels of plasma IL-21, IFN-γ and the frequency of peripheral blood activated T cells were measured longitudinally. Following infection with SHIV, the levels of plasma IL-21 and IFN-γ increased, peaked at 17 days postinfection and declined later. Furthermore, IL-21 induced IL-21 receptor (IL-21R) and IFN-γ, perforin, but not granmyze B, expression in CD8+ cells from four selected SHIV-infected RMs. The regulatory effect of IL-21 on CD8+ cell function appeared to be associated with increased levels of STAT3, but not STAT5, phosphorylation in CD8+ cells from SHIV-infected RMs. In parallel, treatment with soluble IL-21R/Fc, an inhibitor of IL-21-induced activation of JAK1/3 and STAT3, abrogated IL-21-induced STAT3 activation and IFN-γ production in CD8+ cells from SHIV-infected RMs in vitro. Our data indicated that IL-21 was a positive regulator of IFN-γ-secreting CD8+ cells and increased the STAT3 phosphorylation, regulating T-cell immunity against acute SHIV infection in RMs. Our findings may provide a new basis for the development of immunotherapies for the control of SHIV/HIV infection.
PeretzY, AlterG, BoisvertMP, HatzakisG, TsoukasCM, BernardNF. Human immunodeficiency virus (HIV)-specific gamma interferon secretion directed against all expressed HIV genes: relationship to rate of CD4 decline. J Virol2005;79:4908–17
2.
WongJK, StrainMC, PorrataR, ReayE, Sankaran-WaltersS, IgnacioCC, RussellT, PillaiSK, LooneyDJ, DandekarS. In vivo CD8+-cell suppression of siv viremia is not mediated by CTL clearance of productively infected cells. PLoS Pathog2010;6:e1000748
3.
CantinEM, HintonDR, ChenJ, OpenshawH. Gamma interferon expression during acute and latent nervous system infection by herpes simplex virus type 1. J Virol1995;69:4898–905
4.
KarupiahG, FredricksonTN, HolmesKL, KhairallahLH, BullerRM. Importance of interferons in recovery from mousepox. J Virol1993;67:4214–26
5.
MüllerU, SteinhoffU, ReisLF, HemmiS, PavlovicJ, ZinkernagelRM, AguetM. Functional role of type I and type II interferons in antiviral defense. Science1994;264:1918–21
6.
WatanabeD, UehiraT, YonemotoH, BandoH, OgawaY, YajimaK, TaniguchiT, KasaiD, NishidaY, ShirasakaT. Sustained high levels of serum interferon-gamma during HIV-1 infection: a specific trend different from other cytokines. Viral Immunol2010;23:619–25
7.
PahwaS. Role of common gamma chain utilizing cytokines for immune reconstitution in HIV infection. Immunol Res2007;38:373–86
8.
AiutiF, MezzaromaI. Failure to reconstitute CD4+ T-cells despite suppression of HIV replication under HAART. AIDS Rev2006;8:88–97
LevyY, LacabaratzC, WeissL, ViardJP, GoujardC, LelièvreJD, BouéF, MolinaJM, RouziouxC, Avettand-FénoêlV, CroughsT, BeqS, ThiébautR, ChêneG, MorreM, DelfraissyJF. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest2009;119:997–1007
11.
SeretiI, DunhamRM, SpritzlerJ, AgaE, ProschanMA, MedvikK, BattagliaCA, LandayAL, PahwaS, FischlMA, AsmuthDM, TenorioAR, AltmanJD, FoxL, MoirS, MalaspinaA, MorreM, BuffetR, SilvestriG, LedermanMM; ACTG 5214 Study Team. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood2009;113:6304–14
12.
MarchettiG, FranzettiF, GoriA. Partial immune reconstitution following highly active antiretroviral therapy: can adjuvant interleukin-2 fill the gap?J Antimicrob Chemother2005;55:401–9
13.
FengYM, WanYM, LiuLX, QiuC, MaPF, PengH, RuanYH, HanLF, HongKX, XingH, ShaoYM. HIV-specific IL-2(+) and/or IFN-gamma(+) CD8(+) T cell responses during chronic HIV-1 infection in former blood donors. Biomed Env Sci2010;23:391–401
14.
AhmadA, AhmadR, IannelloA, TomaE, MorissetR, SindhuST. IL-15 and HIV infection: lessons for immunotherapy and vaccination. Curr HIV Res2005;3:261–70
15.
MuellerYM, BojczukPM, HalsteadES, KimAH, WitekJ, AltmanJD, KatsikisPD. IL-15 enhances survival and function of HIV-specific CD8+ cells. Blood2003;101:1024–9
16.
Parrish-NovakJ, DillonSR, NelsonA, HammondA, SprecherC, GrossJA, JohnstonJ, MaddenK, XuW, WestJ, SchraderS, BurkheadS, HeipelM, BrandtC, KuijperJL, KramerJ, ConklinD, PresnellSR, BerryJ, ShiotaF, BortS, HamblyK, MudriS, CleggC, MooreM, GrantFJ, Lofton-DayC, GilbertT, RayondF, ChingA, YaoL, SmithD, WebsterP, WhitmoreT, MaurerM, KaushanskyK, HollyRD, FosterD. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature2000;408:57–63
17.
OnodaT, RahmanM, NaraH, ArakiA, MakabeK, TsumotoK, KumagaiI, KudoT, IshiiN, TanakaN, SugamuraK, HayasakaK, AsaoH. Human CD4+ central and effector memory T cells produce IL-21: effect on cytokine-driven proliferation of CD4+ T cell subsets. Int Immunol2007;19:1191–9
18.
SutoA, KashiwakumaD, KagamiS, HiroseK, WatanabeN, YokoteK, SaitoY, NakayamaT, GrusbyMJ, IwamotoI, NakajimaH. Development and characterization of IL-21-producing CD4+ T cells. J Exp Med2008;205:1369–79
19.
LintermanMA, BeatonL, YuD, RamiscalRR, SrivastavaM, HoganJJ, VermaNK, SmythMJ, RigbyRJ, VinuesaCG. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med2010;207:353–63
20.
LiuZ, YangL, CuiY, WangX, GuoC, HuangZ, KanQ, LiuZ, LiuY. Il-21 enhances NK cell activation and cytolytic activity and induces Th17 cell differentiation in inflammatory bowel disease. Inflamm Bowel Dis2009;15:1133–44
21.
WilliamsLD, BansalA, SabbajS, HeathSL, SongW, TangJ, ZajacAJ, GoepfertPA. Interleukin-21-producing HIV-1-specific CD8T cells are preferentially seen in elite controllers. J Virol2011;85:2316–24
22.
ChevalierMF, JülgB, PyoA, FlandersM, RanasingheS, SoghoianDZ, KwonDS, RychertJ, LianJ, MullerMI, CutlerS, McAndrewE, JessenH, PereyraF, RosenbergES, AltfeldM, WalkerBD, StreeckH. HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ cell function. J Virol2011;85:733–41
23.
YueFY, LoC, SakhdariA, LeeEY, KovacsCM, BenkoE, LiuJ, SongH, JonesRB, ShethP, ChegeD, KaulR, OstrowskiMA. HIV-specific IL-21 producing CD4+ T cells are induced in acute and chronic progressive HIV infection and are associated with relative viral control. J Immunol2010;185:498–506
24.
PorichisF, KwonDS, ZupkoskyJ, TigheDP, McMullenA, BrockmanMA, PavlikDF, Rodriguez-GarciaM, PereyraF, FreemanGJ, KavanaghDG, KaufmannDE. Responsiveness of HIV-specific CD4 T cells to PD-1 blockade. Blood2011;118:965–74
25.
FilatenkovAA, JacovettyEL, FischerUB, CurtsingerJM, MescherMF, IngulliE. CD4 T cell-dependent conditioning of dendritic cells to produce IL-12 results in CD8-mediated graft rejection and avoidance of tolerance. J Immunol2005;174:6909–17
26.
ZengR, SpolskiR, FinkelsteinSE, OhS, KovanenPE, HinrichsCS, Pise-MasisonCA, RadonovichMF, BradyJN, RestifoNP, BerzofskyJA, LeonardWJ. Synergy of IL-21 and IL-15 in regulating CD8+ cell expansion and function. J Exp Med2005;201:139–48
27.
BradyJ, HayakawaY, SmythMJ, NuttSL. IL-21 induces the functional maturation of murine NK cells. J Immunol2004;172:2048–58
28.
WursterAL, RodgersVL, SatoskarAR, WhittersMJ, YoungDA, CollinsM, GrusbyMJ. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells. J Exp Med2002;196:969–77
29.
HoggAE, BowickGC, HerzogNK, CloydMW, EndsleyJJ. Induction of granulysin in CD8+ cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1. J Leukoc Biol2009;86:1191–203
30.
KasaianMT, WhittersMJ, CarterLL, LoweLD, JussifJM, DengB, JohnsonKA, WitekJS, SenicesM, KonzRF, WursterAL, DonaldsonDD, CollinsM, YoungDA, GrusbyMJ. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity2002;16:559–69
31.
GarcíaA, SiddappaNB, LiQ, HaaseAT, PaulK, StroudF, ZhangX, FountainJA, VillingerF, NovembreFJ, ElseJG, Evan SecorW, RuprechtRM. AIDS and optic neuritis in a rhesus monkey infected with the R5 clade C SHIV-1157ipd3N4. J Med Primatol2010;39:356–60
32.
SantosuossoM, RighiE, HillED, LeblancPR, KodishB, MylvaganamHN, SiddappaNB, StevcevaL, HuSL, GhebremichaelM, ChenineAL, HovavAH, RuprechtRM, PoznanskyMC. R5-SHIV induces multiple defects in T cell function during early infection of rhesus macaques including accumulation of T reg cells in lymph nodes. PLoS One2011;6:e18465
33.
HumbertM, RasmussenRA, SongR, OngH, SharmaP, ChenineAL, KramerVG, SiddappaNB, XuW, ElseJG, NovembreFJ, StrobertE, O'NeilSP, RuprechtRM. SHIV-1157i and passaged progeny viruses encoding R5 HIV-1 clade C env cause AIDS in rhesus monkeys. Retrovirology2008;5:94
Van RompayKK. Antiretroviral drug studies in nonhuman primates: a valid animal model for innovative drug efficacy and pathogenesis experiments. AIDS Rev2005;7:67–83
36.
GeorgeMD, SankaranS, ReayE, GelliAC, DandekarS. High-throughput gene expression profiling indicates dysregulation of intestinal cell cycle mediators and growth factors during primary simian immunodeficiency virus infection. Virology2003;312:84–94
37.
SchaeferTM, FullerCL, BasuS, FallertBA, PovedaSL, SanghaviSK, ChoiYK, KirschnerDE, FeingoldE, ReinhartTA. Increased expression of interferon-inducible genes in macaque lung tissues during simian immunodeficiency virus infection. Microbes Infect2006;8:1839–50
38.
LeuteneggerCM, HigginsJ, MatthewsTB, TarantalAF, LuciwPA, PedersenNC, NorthTW. Real-time TaqMan PCR as a specific and more sensitive alternative to the branched-chain DNA assay for quantitation of simian immunodeficiency virus RNA. AIDS Res Hum Retroviruses2001;17:243–51
39.
NiuMT, BethelJ, HolodniyM, StandifordHC, SchnittmanSM. Zidovudine treatment in patients with primary (acute) human immunodeficiency virus type 1 infection: a randomized, double-blind, placebo-controlled trial. DATRI 002 Study Group. Division of AIDS Treatment Research Initiative. J Infect Dis1998;178:80–91
40.
DeeksSG, KitchenCM, LiuL, GuoH, GasconR, NarváezAB, HuntP, MartinJN, KahnJO, LevyJ, McGrathMS, HechtFM. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood2004;104:942–7
41.
FrankI, PiatakMJr, StoesselH, RomaniN, BonnyayD, LifsonJD, PopeM. Infectious and whole inactivated simian immunodeficiency viruses interact similarly with primate dendritic cells (DCs): differential intracellular fate of virions in mature and immature DCs. J Virol2002;76:2936–51
42.
StrengellM, SarenevaT, FosterD, JulkunenI, MatikainenS. IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. J Immunol2002;169:3600–5
43.
DattaS, SarvetnickNE. IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms. PLoS One2008;3:e3118
CrostarosaF, AravantinouM, AkpoghenetaOJ, JasnyE, ShawA, KenneyJ, PiatakM, LifsonJD, TeitelbaumA, HuL, ChudolijA, ZydowskyTM, BlanchardJ, GettieA, RobbianiM. A macaque model to study vaginal HSV-2/immunodeficiency virus co-infection and the impact of HSV-2 on microbicide efficacy. PLoS One2009;4:e8060
46.
LivakKJ, SchmittgenTD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods2001;25:402–8
47.
IannelloA, BoulasselMR, SamaraniS, DebbecheO, TremblayC, TomaE, RoutyJP, AhmadA. Dynamics and consequences of IL-21 production in HIV-infected individuals: a longitudinal and cross-sectional study. J Immunol2010;184:114–26
48.
YiJS, CoxMA, ZajacAJ. Interleukin-21: a multifunctional regulator of immunity to infections. Microbes Infect2010;12:1111–9
49.
StrengellM, MatikainenS, SirénJ, LehtonenA, FosterD, JulkunenI, SarenevaT. IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol2003;170:5464–9
50.
ThompsonJA, CurtiBD, RedmanBG, BhatiaS, WeberJS, AgarwalaSS, SieversEL, HughesSD, DeVriesTA, HausmanDF. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol2008;26:2034–9
51.
GrünwaldV, DesarIM, HaanenJ, FiedlerW, MouritzenU, OlsenMW, van HerpenCM. A phase I study of recombinant human interleukin-21 (rIL-21) in combination with sunitinib in patients with metastatic renal cell carcinoma (RCC). Acta Oncol2011;50:121–6
52.
PallikkuthS, RogersK, VillingerF, DosteriiM, VaccariM, FranchiniG, PahwaR, PahwaS. Interleukin-21 administration to rhesus macaques chronically infected with simian immunodeficiency virus increases cytotoxic effector molecules in T cells and NK cells and enhances B cell function without increasing immune activation or viral replication. Vaccine2011;29:9229–38
53.
WuZ, KimHP, XueHH, LiuH, ZhaoK, LeonardWJ. Interleukin-21 receptor gene induction in human T cells is mediated by T-cell receptor-induced Sp1 activity. Mol Cell Biol2005;25:9741–52
54.
NaraH, OnodaT, RahmanM, ArakiA, JulianaFM, TanakaN, AsaoH. Regulation of interleukin-21 receptor expression and its signal transduction by WSB-2. Biochem Biophys Res Commun2010;392:171–7
55.
IannelloA, BoulasselMR, SamaraniS, TremblayC, TomaE, RoutyJP, AhmadA. IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication. J Leukoc Biol2010;87:857–67
56.
WhiteL, KrishnanS, StrboN, LiuH, KolberMA, LichtenheldMG, PahwaRN, PahwaS. Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV). Blood2007;109:3873–80
57.
FrederiksenKS, LundsgaardD, FreemanJA, HughesSD, HolmTL, SkrumsagerBK, PetriA, HansenLT, McArthurGA, DavisID, SkakK. IL-21 induces in vivo immune activation of NK cells and CD8(+) T cells in patients with metastatic melanoma and renal cell carcinoma. Cancer Immunol Immunother2008;57:1439–49
