Major histocompatibility complex (MHC) class II expression is critical for the presentation of antigens in the immune response to viral infection. Consequently, some viruses regulate the MHC class II-mediated presentation of viral antigens as a mechanism of immune escape. In this study, we found that Coxsackievirus B3 (CVB3) infection transiently increased IK expression, which reduced the expression of MHC class II (I-A/I-E) on splenic B cells. Interestingly, CVB3-induced IK elevated cAMP, a downstream molecule of the G protein-coupled receptors, which inhibited MHC class II presentation on B cells. Transgenic mice expressing truncated IK showed lower expression of MHC class II on B cells than did wild-type mice after CVB3 infection. Taken together, these results imply that IK plays a role in downregulating MHC class II expression on B cells during CVB3 infection through the induction of cAMP.
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References
1.
AbendrothA, SlobedmanB, LeeE, MellinsE, WallaceM, ArvinAM. Modulation of major histocompatibility class II protein expression by varicella-zoster virus. J Virol, 2000; 74:1900–1907.
2.
AssierEH, Bouzinba-SegardH, StolzenbergMCet al.Isolation, sequencing and expression of RED, a novel human gene encoding an acidic–basic dipeptide repeat. Gene, 1999; 230:145–154.
3.
BishopGA. Requirements of class II-mediated B cell differentiation for class II cross-linking and cyclic AMP. J Immunol, 1991; 147:1107–1114.
4.
BuflerP, Gamboni-RobertsonF, AzamT, KimSH, DinarelloCA. Interleukin-1 homologues IL-1F7b and IL-18 contain functional mRNA instability elements within the coding region responsive to lipopolysaccharide. Biochem J, 2004; 381:503–510.
5.
CalebiroD, NikolaevVO, LohseMJ. Imaging of persistent cAMP signaling by internalized G protein-coupled receptors. J Mol Endocrinol, 2010; 45:1–8.
6.
CambierJC, NewellMK, JustementLB, McGuireJC, LeachKL, ChenZZ. Ia binding ligand and cAMP stimulate nuclear translocation of PKC in B lymphocytes. Nature, 1987; 327:629–632.
7.
CaoLX, Le Bousse-KerdilesMC, ClayD, OshevskiS, JasminC, KriefP. Implication of a new molecule IK in CD34+ hematopoietic progenitor cell proliferation and differentiation. Blood, 1997; 89:3615–3623.
8.
CarbonettiNH. Pertussis toxin and adenylate cyclase toxin: Key virulence factors of Bordetella pertussis and cell biology tools. Future Microbiol, 2010; 5:455–469.
9.
CarbonettiNH, ArtamonocaGV, AndreasenC, DudleyE, MaysRM, WorthingtonZE. Suppression of serum antibody responses by pertussis toxin after respiratory tract colonization by Bordetella pertussis and identification of an immunodominant lipoprotein. Infect Immun, 2004; 72:3350–3358.
10.
ChangCH, GuerderS, HongSC, van EwijkW, FlavellRA. Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity, 1996; 4:167–178.
11.
CoutinhoGC, Durieu-TrautmannO, StrosbergAD, CouraudPO. Catecholamines stimulate the IFN-gamma-induced class II MHC expression on bovine brain capillary endothelial cells. J Immunol, 1991; 147:2525–2529.
12.
el BayaA, LinnermannR, von Olleschik-ElbheimL, SchmidtMA. Pertussis toxin entry into cells and enzymatic activity. Adv Exp Med Biol, 1997; 419:83–86.
13.
GrünK, MarkovaB, BöhmerFD, BerndtA, KosmehlH, LeipnerC. Elevated expression of PDGF-C in coxsackievirus B3-induced chronic myocarditis. Eur Heart J, 2005; 26:728–739.
14.
HartonJA, TingJP. Class II transactivator: Mastering the art of major histocompatibility complex expression. Mol Cell Biol, 2000; 20:6185–6194.
15.
HegdeNR, ChevalierMS, JohnsonDC. Viral inhibition of MHC class II antigen presentation. Trends Immunol, 2003; 24:278–285.
16.
HeoDH, BaekIJ, KangHJet al.Cadmium regulates copper homoeostasis by inhibition the activity of Mac1, a transcriptional activator of the copper regulon in Saccharomyces cerevisiae. Biochem J, 2010; 431:257–265.
17.
HuberS. Host immune responses to coxsackievirus B3. Curr Top Microbiol Immunol, 2008; 323:199–221.
18.
HühnMH, HultcrantzM, LindK, LjunggrenHG, MalmbergKJ, Flodström-TullbergM. IFN-γ production dominates the early human natural killer cell response to Coxsackievirus infection. Cell Microbiol, 2008; 10:426–436.
19.
InfantinoS, MoeppsB, ThelenM. Expression and regulation of the orphan receptor RDC1 and its putative ligand in human dendritic and B cells. J immunol, 2006; 176:2197–2207.
20.
IvashkivLB, AyresA, GlimcherLH. Inhibition of IFN-gamma induction of class II MHC genes by cAMP and prostaglandins. Immunopharmacology, 1994; 27:67–77.
KemballCC, HarkinsS, WhitmireJK, FlynnCT, FeuerR, WhittonJL. Coxsackievirus B3 inhibits antigen presentation in vivo, exerting a profound and selective effect on the MHC class I pathway. PLoS One, 2009; 5:e1000618.
23.
KemballCC, AlirezaeiM, WhittonJL. Type B coxsackieviruses and their interactions with the innate and adaptive immune systems. Future Microbiol, 2010; 5:1329–1347.
24.
KimDS, NamJH. Application of attenuated coxsackievirus B3 as a viral vector system for vaccines and gene therapy. Hum Vaccin, 2011; 7:410–416.
25.
KriefP, BoucheixC, BillardC, MichalZ, Van AgthovenA, FiersW, AzzaroneB. Modulation of expression of class II histocompatibility antigen by secretion of a cellular inhibitor in K562 leukemia cells. Eur J Immunol, 1987; 17:1021–1025.
26.
LeipnerC, BorchersM, MerkleI, StelznerA. Coxsackievirus B3-induced myocarditis in MHC class II-deficient mice. J Hum Virol, 1999; 2:102–114.
27.
LiK, AndersonKJ, PengQet al.Cyclic AMP plays a critical role in C3a-receptor-mediated regulation of dendritic cells in antigen uptake and T-cell stimulation. Blood, 2008; 112:5084–5094.
28.
LiL, DufourAP. Using IFN-γ as a biomarker for detecting exposure to viral pathogens. Curr Microbiol, 2008; 56:84–88.
MeissnerM, WhitesideTL, KaufmannR, SeligerB. CIITA versus IFN-gamma induced MHC class II expression in head and neck cancer cells. Arch Dermatol Res, 2009; 301:189–193.
33.
MuraokaM, HaseqawaH, KohnoMet al.IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice. Arthritis Rheum, 2006; 54:3591–3600.
34.
NaumannU, CameroniE, PruensterMet al.CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS One, 2010; 5:e9175.
35.
NegishiH, OsawaT, OgamiKet al.A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity. Proc Natl Acad Sci USA, 2008; 105:20446–20451.
36.
NoldMF, Nold-PetryCA, ZeppJA, PalmerBE, BuflerP, DinarelloCA. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol, 2010; 11:1014–1022.
37.
ParkJH, KimDS, ChoYJet al.Attenuation of coxsackievirus B3 by VP2 mutation and its application as a vaccine against virus-induced myocarditis and pancreatitis. Vaccine, 2009; 27:1974–1983.
38.
PiskurichJF, GilbertCA, AshleyBDet al.Expression of the MHC class II transactivator (CIITA) type IV promoter in B lymphocytes and regulation by IFN-γMol Immunol, 2006; 43:519–528.
39.
PlanzO, EhlS, FurrerE, HorvathE, BründlerMA, HengartnerH, ZinkernagelRM. A critical role for neutralizing-antibody-producing B cells, CD4+ T cells and interferons in persistent and acute infections of mice with lymphocytic choriomeningitis virus: Implications for adoptive immunotherapy of virus carriers. Proc Natl Acad Sci USA, 1997; 94:6874–6879.
RahnefeldA, EbsteinF, AlbrechtNet al.Antigen-presentation capacity of dendritic cells is impaired in ongoing enterovirus myocarditis. Eur J Immunol, 2011; 41:2774–2781.
42.
ReithW, LeibundGut-LandmannS, WaldburgerJM. Regulation of MHC class II gene expression by the class II transactivator. Nat Rev Immunol, 2005; 5:793–806.
43.
ReithW, MachB. The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol, 2001; 19:331–373.
44.
SekoY, TsuchimochiH, NakamuraTet al.Expression of major histocompatibility complex class I antigen in murine ventricular myocytes infected with Coxsackievirus B3. Circ Res, 1990; 67:360–367.
45.
ShimSH, KimYJ, KimDS, NamJH. Development of a gene therapy method for cervical cancer using attenuated coxsackievirus B3 as a vector system. J Bacteriol Virol, 2011; 41:123–130.
Thanthrige-DonN, ReadLR, Abdul-CareemMF, MohammadiH, MallickAI, SharifS. Marek's disease virus influences the expression of genes associated with IFN-gamma-inducible MHC class II expression. Viral Immunol, 2010; 23:227–232.
49.
VendrenneJ, AssierE, PerenoRet al.Inhibitor (IK) of IFN-γ induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line. Oncogene, 1997; 14:1453–1461.
50.
VinuesaCG, TangyeSG, MoserB, MackayCR. Follicular B helper T cells in antibody responses and antoimmunity. Nat Rev Immunol, 2005; 5:853–865.
51.
WalkerLJ, SewellAK, KlenermanP. T cell sensitivity and the outcome of viral infection. Clin Exp Immunol, 2010; 159:245–255.
52.
WhyHJ, MeanyBT, RichardsonPJet al.Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy. Circulation, 1994; 89:2582–2589.
53.
XuY, RavidK, SimthBD. Major histocompatibility class II transactivator expression in smooth muscle cells from A2b adenosine receptor knock-out mice. J Biol Chem, 2008; 283:14213–14220.
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