Type I interferons (IFN-αβ) are pleiotropic cytokines critical for antiviral host defense, and the timing and magnitude of their production involve a complex interplay between host and pathogen factors. Mouse cytomegalovirus (a β-herpesvirus) is a persistent virus that induces a biphasic IFN-αβ response during the first days of infection. The cell types and molecular mechanisms governing these 2 phases are unique, with splenic stromal cells being a major source of initial IFN-αβ, requiring communication with B cells expressing lymphotoxin, a tumor necrosis factor family cytokine. Here we review the factors that regulate this lymphotoxin–IFN-αβ “axis” during cytomegalovirus infection, highlight how stroma-derived IFN-αβ contributes in other models, and discuss how deregulation of this axis can lead to pathology in some settings.
BenedictCA, De TrezC, SchneiderK, HaS, PattersonG, WareCF. 2006. Specific remodeling of splenic architecture by cytomegalovirus. PLoS Pathog, 2,3:e16.
5.
BeutlerB, GeorgelP, RutschmannS, JiangZ, CrokerB, CrozatK. 2005. Genetic analysis of innate resistance to mouse cytomegalovirus (MCMV)Brief Funct Genomic Proteomic, 4,3:203–213.
6.
BrowneEP, WingB, ColemanD, ShenkT. 2001. Altered cellular mRNA levels in human cytomegalovirus-infected fibroblasts: viral block to the accumulation of antiviral mRNAs. J Virol, 75:12319–12330.
7.
ChongKT, GresserI, MimsCA. 1983. Interferon as a defence mechanism in mouse cytomegalovirus infection. J Gen Virol, 64,Pt 2:461–464.
8.
DalodM, HamiltonT, SalomonR, Salazar-MatherTP, HenrySC, HamiltonJD, BironCA. 2003. Dendritic cell responses to early murine cytomegalovirus infection: subset functional specialization and differential regulation by interferon alpha/beta. J Exp Med, 197,7:885–898.
9.
DalodM, Salazar-MatherTP, MalmgaardL, LewisC, Asselin-PaturelC, BriereF, TrinchieriG, BironCA. 2002. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J Exp Med, 195,4:517–528.
10.
DeFilippisVR. 2007. Induction and evasion of the type I interferon response by cytomegaloviruses. Adv Exp Med Biol, 598:309–324.
11.
DeFilippisVR, AlvaradoD, SaliT, RothenburgS, FruhK. 2010. Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J Virol, 84,1:585–598.
12.
DejardinE, DroinNM, DelhaseM, HaasE, CaoY, MakrisC, LiZW, KarinM, WareCF, GreenDR. 2002. The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. Immunity, 17,4:525–535.
13.
EttingerR, BrowningJL, MichieSA, van EwijkW, McDevittHO. 1996. Disrupted splenic architecture, but normal lymph node development in mice expressing a soluble lymphotoxin-b receptor-IgG1 fusion protein. Proc Natl Acad Sci USA, 93:13102–13107.
GrundyJE, TrapmanJ, AllanJE, ShellamGR, MeliefCJ. 1982. Evidence for a protective role of interferon in resistance to murine cytomegalovirus and its control by non-H-2-linked genes. Infect Immun, 37,1:143–150.
HsuKM, PrattJR, AkersWJ, AchilefuSI, YokoyamaWM. 2009. Murine cytomegalovirus displays selective infection of cells within hours after systemic administration. J Gen Virol, 90,Pt 1:33–43.
18.
IshikawaH, BarberGN. 2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature, 455,7213:674–678.
19.
IversenAC, NorrisPS, WareCF, BenedictCA. 2005. Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-beta. J Immunol, 175,11:7568–7574.
20.
JarvisMA, BortonJA, KeechAM, WongJ, BrittWJ, MagunBE, NelsonJA. 2006. Human cytomegalovirus attenuates interleukin-1beta and tumor necrosis factor alpha proinflammatory signaling by inhibition of NF-kappaB activation. J Virol, 80,11:5588–5598.
21.
KaiserWJ, UptonJW, MocarskiES. 2008. Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors. J Immunol, 181,9:6427–6434.
22.
KatakaiT, HaraT, SugaiM, GondaH, ShimizuA. 2004. Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes. J Exp Med, 200,6:783–795.
23.
KernER. 2006. Pivotal role of animal models in the development of new therapies for cytomegalovirus infections. Antiviral Res, 71,2–3:164–171.
24.
KernER, OlsenGA, OverallJCJr., GlasgowLA. 1978. Treatment of a murine cytomegalovirus infection with exogenous interferon, polyinosinic-polycytidylic acid, and polyinosinic-polycytidylic acid-poly-L-lysine complex. Antimicrob Agents Chemother, 13,2:344–346.
25.
KraalG, MebiusR. 2006. New insights into the cell biology of the marginal zone of the spleen. Int Rev Cytol, 250:175–215.
26.
LenacT, ArapovicJ, TravenL, KrmpoticA, JonjicS. 2008. Murine cytomegalovirus regulation of NKG2D ligands. Med Microbiol Immunol, 197,2:159–166.
27.
LinkA, VogtTK, FavreS, BritschgiMR, Acha-OrbeaH, HinzB, CysterJG, LutherSA. 2007. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol, 8,11:1255–1265.
28.
LoewendorfA, BenedictCA. 2010. Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything. J Intern Med, 267:483–501.
29.
LonghiMP, TrumpfhellerC, IdoyagaJ, CaskeyM, MatosI, KlugerC, SalazarAM, ColonnaM, SteinmanRM. 2009. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med, 206,7:1589–1602.
30.
MackayF, MajeauGR, LawtonP, HochmanPS, BrowningJL. 1997. Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice. Eur J Immunol, 27,8:2033–2042.
31.
ManiatisT, FalvoJV, KimTH, KimTK, LinCH, ParekhBS, WatheletMG. 1998. Structure and function of the interferon-beta enhanceosome. Cold Spring Harb Symp Quant Biol, 63:609–620.
32.
MarshallEE, GeballeAP. 2009. Multifaceted evasion of the interferon response by cytomegalovirus. J Interferon Cytokine Res, 29,9:609–619.
33.
MebiusRE, KraalG. 2005. Structure and function of the spleen. Nat Rev Immunol, 5,8:606–616.
34.
MercerJA, WileyCA, SpectorDH. 1988. Pathogenesis of murine cytomegalovirus infection: identification of infected cells in the spleen during acute and latent infections. J Virol, 62:987–997.
35.
MuellerSN, GermainRN. 2009. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat Rev Immunol, 9,9:618–629.
36.
MuellerSN, Hosiawa-MeagherKA, KoniecznyBT, SullivanBM, BachmannMF, LocksleyRM, AhmedR, MatloubianM. 2007. Regulation of homeostatic chemokine expression and cell trafficking during immune responses. Science, 317,5838:670–674.
37.
NakanoH, OshimaH, ChungW, Williams-AbbottL, WareC, YagitaH, OkumuraK. 1996. TRAF5, an activator of NF-kB and putative signal transducer for the lymphotoxin-b receptor. J Biol Chem, 271:14661–14664.
38.
NguyenKB, Salazar-MatherTP, DalodMY, Van DeusenJB, WeiXQ, LiewFY, CaligiuriMA, DurbinJE, BironCA. 2002. Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol, 169,8:4279–4287.
39.
OrangeJS, BironCA. 1996. Characterization of early IL-12, IFN-alpha beta, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J Immunol, 156,12:4746–4756.
40.
OrangeJS, WangB, TerhorstC, BironCA. 1995. Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J Exp Med, 182,4:1045–1056.
41.
OsbornJE, MedearisDNJr.1966. Studies of relationship between mouse cytomegalovirus and interferon. Proc Soc Exp Biol Med, 121,3:819–824.
42.
PereiraL, MaidjiE, McDonaghS, TabataT. 2005. Insights into viral transmission at the uterine-placental interface. Trends Microbiol, 13,4:164–174.
43.
PichlmairA, Reis e SousaC. 2007. Innate recognition of viruses. Immunity, 27,3:370–383.
44.
PowersC, FruhK. 2008. Rhesus CMV: an emerging animal model for human CMV. Med Microbiol Immunol, 197,2:109–115.
45.
RandallTD, CarragherDM, Rangel-MorenoJ. 2008. Development of secondary lymphoid organs. Annu Rev Immunol, 26:627–650.
46.
RebsamenM, HeinzLX, MeylanE, MichalletMC, SchroderK, HofmannK, VazquezJ, BenedictCA, TschoppJ. 2009. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB. EMBO Rep, 10,8:916–922.
47.
SacherT, PodlechJ, MohrCA, JordanS, RuzsicsZ, ReddehaseMJ, KoszinowskiUH. 2008. The major virus-producing cell type during murine cytomegalovirus infection, the hepatocyte, is not the source of virus dissemination in the host. Cell Host Microbe, 3,4:263–272.
48.
SanjoH, ZajoncDM, BradenR, NorrisPS, WareCF. 2010. Allosteric regulation of the ubiquitin:NIK and ubiquitin:TRAF3 E3 ligases by the lymphotoxin-beta receptor. J Biol Chem, 285,22:17148–17155.
49.
ScalzoAA, CorbettAJ, RawlinsonWD, ScottGM, Degli-EspostiMA. 2007. The interplay between host and viral factors in shaping the outcome of cytomegalovirus infection. Immunol Cell Biol, 85,1:46–54.
50.
ScandellaE, BolingerB, LattmannE, MillerS, FavreS, LittmanDR, FinkeD, LutherSA, JuntT, LudewigB. 2008. Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nat Immunol, 9,6:667–675.
51.
SchilteC, CoudercT, ChretienF, SourisseauM, GangneuxN, Guivel-BenhassineF, KraxnerA, TschoppJ, HiggsS, MichaultA, Arenzana-SeisdedosF, ColonnaM, PedutoL, SchwartzO, LecuitM, AlbertML. 2010. Type I IFN controls chikungunya virus via its action on nonhematopoietic cells. J Exp Med, 207,2:429–442.
52.
SchneiderK, LoewendorfA, De TrezC, FultonJ, RhodeA, ShumwayH, HaS, PattersonG, PfefferK, NedospasovSA, WareCF, BenedictCA. 2008. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe, 3,2:67–76.
53.
StarasSA, DollardSC, RadfordKW, FlandersWD, PassRF, CannonMJ. 2006. Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin Infect Dis, 43,9:1143–1151.
54.
TakaokaA, WangZ, ChoiMK, YanaiH, NegishiH, BanT, LuY, MiyagishiM, KodamaT, HondaK, OhbaY, TaniguchiT. 2007. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature, 448,7152:501–505.
TaylorRT, BresnahanWA. 2006. Human cytomegalovirus immediate-early 2 protein IE86 blocks virus-induced chemokine expression. J Virol, 80,2:920–928.
60.
ThanosD, ManiatisT. 1995. Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell, 83,7:1091–1100.
61.
TomeiAA, SiegertS, BritschgiMR, LutherSA, SwartzMA. 2009. Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node microenvironment. J Immunol, 183,7:4273–4283.
62.
TumanovAV, GrivennikovSI, ShakhovAN, RybtsovSA, KorolevaEP, TakedaJ, NedospasovSA, KuprashDV. 2003a. Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting. Immunol Rev, 195:106–116.
63.
TumanovAV, KuprashDV, NedospasovSA. 2003b. The role of lymphotoxin in development and maintenance of secondary lymphoid tissues. Cytokine Growth Factor Rev, 14,3–4:275–288.
64.
TyznikAJ, TupinE, NagarajanNA, HerMJ, BenedictCA, KronenbergM. 2008. Cutting edge: the mechanism of invariant NKT cell responses to viral danger signals. J Immunol, 181,7:4452–4456.
65.
VanArsdaleTL, VanArsdaleSL, ForceWR, WalterBN, MosialosG, KieffE, ReedJC, WareCF. 1997. Lymphotoxin-b receptor signaling complex: role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kB. Proc Natl Acad Sci USA, 94:2460–2465.
66.
VaraniS, FrascaroliG, LandiniMP, Soderberg-NauclerC. 2009. Human cytomegalovirus targets different subsets of antigen-presenting cells with pathological consequences for host immunity: implications for immunosuppression, chronic inflammation and autoimmunity. Rev Med Virol, 19,3:131–145.
67.
WareCF. 2005. NETWORK COMMUNICATIONS: Lymphotoxins, LIGHT, and TNF. Annu Rev Immunol, 23:787–819.
68.
WesleyJD, TessmerMS, ChaukosD, BrossayL. 2008. NK cell-like behavior of Valpha14i NK T cells during MCMV infection. PLoS Pathog, 4,7:e1000106.
69.
YanaiH, SavitskyD, TamuraT, TaniguchiT. 2009. Regulation of the cytosolic DNA-sensing system in innate immunity: a current view. Curr Opin Immunol, 21,1:17–22.
70.
ZindlCL, KimTH, ZengM, ArchambaultAS, GraysonMH, ChoiK, SchreiberRD, ChaplinDD. 2009. The lymphotoxin LTalpha(1)beta(2) controls postnatal and adult spleen marginal sinus vascular structure and function. Immunity, 30,3:408–420.
