Virulence3:7,610–620;November15,2012;G2012LandesBioscience Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C Phyllis T. Losikoff, Alyssa A. Self and Stephen H. Gregory* DepartmentofMedicine;RhodeIslandHospitalandtheWarrenAlpertMedicalSchoolatBrownUniversity;Providence,RIUSA Keywords: hepatitis C, chronic liver disease, dendritic cells, FoxP3+ regulatory T cells, tolerance Abbreviations: CCL, chemokine ligand; CCR, chemokine receptor; FoxP3, transcription factor forkhead box P3; HCV, hepatitis C virus; IFN, interferon; IL, interleukin; iT cell, inducible regulatory T cell; mDCs, myeloid dendritic cells; nT cell, natural reg reg regulatory T cell; NS, non-structural; pDCs, plasmacytoid dendritic cells; T cells, effector T cells; TLR, toll-like receptor; eff TGF-β, transforming growth factor-beta technology required to ensure a safe blood supply are elusive for Hepatitis C virus (HCV) is a small, enveloped RNA virus and a most developing countries where prevalence of HCV infection majorcauseofchronicliverdisease.ResolutionofprimaryHCV infectionsdependsuponthevigorousresponsesofCD4+and can be as high as 20% of the population.5 Unfortunately, while CD8+ T cells to multiple viral epitopes. Although such broad- only 20% of patients resolve infection spontaneously, the vast based responses are readily detected early during the course majority develops chronic disease.3 Standard hepatitis C of infection regardless of clinical outcome, they are not treatment consists of the combined administration of maintained in individuals who develop chronic disease. PEGylated interferon (IFN) and ribavirin. The response to Ostensibly, a variety of factors contribute to the diminished conventional therapy varies widely, however, and is often T cell responses observed in chronic, HCV-infected patients accompanied by significant side effects. Only an estimated 45– includingimpaireddendriticcellfunctionandtheinductionof 50% of all patients infected with HCV genotype 1 experience a CD4+FoxP3+ regulatory T cells. Overwhelming evidence sustained virologic response upon treatment withdrawal.6 suggests that the complex interaction of dendritic cells and Treatments that include new protease inhibitors, e.g., telaprevir regulatory T cells plays a critical role in the pathogenesis of and boceprevir, in conjunction with PEGylated IFN and chronic hepatitis C. ribavirin increase the sustained virologic response up to 80% in patients infected with HCV genotype 1.7 HCV-related premature death and morbidity in US patients under65yofageareexpectedtoincrease2-to3-foldbetweenthe Introduction years 2010 and 2019 at a societal cost exceeding $55 billion.8 Spontaneous clearance is affected by a number of factors that Hepatitis C is an emerging infectious disease caused by hepatitis include: age, ethnicity, sex, hepatitis B virus or human C virus (HCV). HCV is a small enveloped virus whose RNA immunodeficiency virus co-infection and host genetics (e.g., genome consists of a large open reading frame that encodes an HLAhaplotypeandIL28Bgenevariants).9-13Themajorityofnew ~3,000 amino acid poly-protein precursor, which is cleaved by cases in the US occur among young, intravenous drug users. cellular and viral proteases to yield the core, envelope (E1 and Resolution of primary HCV infections is associated with the E2)andnonstructural(NS)proteins(NS1–NS5)(Fig.1).1HCV vigorous responses of HLA class I-restricted (CD8+) and class II- isamajorcauseofchronicliverdiseaseandaprincipalreasonfor restricted (CD4+) T cells to multiple epitopes derived from both livertransplant;approximately170millionpeopleworldwideare structural and non-structural proteins.14 Although such broad- chronically infected.2,3 HCV is primarily contracted through the based responses are readily detected early during the course of transmission of infected blood or body fluids. The risk of infection regardless of clinical outcome, they are not maintained transmissionviabloodandbloodproductsintheUSisnegligible inpatientswhodevelopchronicdisease.15Thus,whileindividuals due to the advent of reliable and mandatory blood screening. who spontaneously clear infection continue to exhibit a Isolated (nosocomial/iatrogenic) outbreaks of hepatitis C proliferative response to a wide range of class I- and class II- continue to occur in US medical facilities, however, emphasizing restricted epitopes, chronically infected patients respond to a the vigilance required to enforce universal precautions and limitednumberonly.16Avarietyoffactorspurportedlycontribute proper sterilization of medical devices.4 The infrastructure and tothediminishedTcellresponsesobservedinchronicallyinfected patientsincluding:viralmutationandescapelinkedtobothCD4 and CD8 T cell failure, CD4 T cell anergy, CD8 T cell *Correspondenceto:StephenH.Gregory;Email:[email protected] exhaustion, induction of FoxP3+ regulatory T cells and/or Submitted:07/16/12;Revised:08/10/12;Accepted:08/13/12 (reg) http://dx.doi.org/10.4161/viru.21823 impaired dendritic cell function.17-26 610 Virulence Volume3Issue7 SPECIALFOCUSREVIEW:DENDRITICCELLS Figure1.HepatitisCvirus:structureandgenomicorganization.Theviralgenomeisenclosedwithinthecoreproteinandsurroundedbyanenvelope composedoflipidandglycoproteins(A).HCVisasmall,envelopedviruswithasingle-stranded,positive-senseRNAgenomethatis~9,600nucleotide baseslongandconsistsofasingleopenreadingframe.The5’,~340nucleotidelong,non-translatedregion(NTR)functionsasaninternalribosomeentry sitethatbindsribosomesincloseproximitytothetranslationstartcodon.TheHCVgenomeencodesa~3,000aminoacidpoly-proteinprecursorthatis cleavedco-andpost-translationallybycellularandviralproteasesintotenproteinproducts:C,core;E1andE2,envelope;NS,nonstructuralproteins (NS1–NS5).Thefunctionofeachcleavageproductisshown(B). Dendritic Cells (DCs) further distinguished by the cell surface expression of CD45R/ B220+CD123brightCD303+ and CD11c+CD1a+CD1c+, respect- DCs are professional antigen presenting cells characterized by ively.28-30 mDCs are short lived relative to pDCs, which have a their potent capacity to elicit primary T cell responses.27 Two slow turnover rate and a relatively long half-life.35 major subsets of DCs are readily purified from human peripheral pDCsandmDCsdiffermarkedlyintheirabilitytocapture, blood: plasmacytoid (p)DCs and conventional or myeloid (m) processandpresentantigens,expressco-stimulatorymolecules DCs.28-30 Each subset represents 0.3–0.5% of the normal human and produce cytokines.34 Freshly isolated pDCs express only peripheral blood mononuclear cell (PBMC) population.28,31 moderate, heterogeneous levels of HLA-DR, ingest antigens mDCs and pDCs originate from myeloid and lymphoid poorly and exhibit diminished allogeneic T cell stimulatory precursors, respectively, residing in the bone marrow.32 pDCs activity in mixed lymphocyte reactions.28 By comparison, have a round morphology similar to secretory lymphocytes and mDCs are 10–50 times more efficient in their ability to closely resemble plasma cells.33-35 mDCs, on the other hand, capture, process and present HLA class I- and class II- exhibit the typical dendritic cell morphology with prominent restricted antigenic determinants (epitopes) to CD8+ and cytoplasmic protrusions and veils. Human pDCs and mDCs are CD4+ T cells.36 www.landesbioscience.com Virulence 611 pDCs and mDCs also differ substantially in terms of Toll-like HCV-infectedpatientsappearsdueinparttotheinabilityofDCs receptor (TLR)expression.33,34,37,38pDCs strongly express TLR-7 trapped in the liver to home the lymph nodes.50,52 andTLR-9intheendosomalcompartmentandrespondtosingle Regardlessoftheirdistribution(i.e.,livervs.peripheralblood), stranded RNA and unmethylated CpG-containing DNA ligands, contradictorydataindicatethatfunctionsofpDCsandmDCsare respectively. Consequently, pDCs are potent mediators of either intact56-63 or impaired36,39,42,44,48,64-74 in patients with antiviral immunity and unique in their capacity to secrete large chronic hepatitis C. Functional impairments include: decreased quantities of type 1 IFN following virus infection.33-35,39-42 Upon IFN-a and IL-12 secretion, increased IL-10 production, lowered TLR ligation, pDCs upregulate HLA-DR and the cell surface expression of HLA-DR and costimulatory molecules such as expression of co-stimulatory molecules (e.g., CD80 and CD86), CD86, decreased allostimulatory activity and increased ability to secrete massive amounts of IFN-a/β, acquire T cell stimulatory prime T cells.36,39,42,44,48-50,64,65,67-69,75-79 Additional studies reg activity, and induce T cell polarization and the production of reported that DCs obtained from chronically-infected patients h1 IFN-c.35,39-41mDCs,ontheotherhand,recognizeviralligands(e. were phenotypically immature and failed to upregulate matura- g., HCV core and NS3) via TLR-2, exhibit elevated HLA-DR tion(costimulatory)markersinresponse tostimulisuchasTNF- levels, specialize in IL-12 production, polarize CD4+ T cells a.66,73 Circulating pDCs in chronic HCV-infected patients toward T and demonstrate potent allogeneic T cell react- exhibit: diminished HLA-DR expression, a markedly reduced h1 ivity.28,37,43-45 In addition, recognition of double-stranded RNA capacity to secrete IFN-a and, consequently, decreased anti-viral virusesviaTLR-3stimulatesthereleaseoflargequantitiesofIL-1, potency.36,39,44,67,68,80 mDCs in chronic HCV infections secrete IL-6 and IL-12, and small amounts of type 1 IFN.46 significantlylowerlevelsofIL-12andincreasedconcentrationsof IL-10, which tends to skew the immune response toward Contribution of DCs to the Pathogenesis tolerance and a reduced ability to induce T-cell proliferation of Hepatitis C andT polarization.36,47,49,67,69,72,75-77,81Thestimulatorypotential h1 of mDCs and the alloreactive response of CD4+ T cells are also Despite extensive investigation, there is no general consensus diminished in chronic HCV infections.44 Although the literature regarding the effects of HCV on DC function.47 The failure of addressing mDCs function during acute HCV infection is most patients to manifest clinical symptoms during the acute limited, patients who exhibit decreased mDC allostimulatory phase of infection suggests, however, that DC functions are activity seem to exhibit an increased chance of developing viral normal at the onset. Moreover, it is generally agreed that the persistence.71 In sharp contrast to chronically infected patients in numberscomprisingboththepDCandmDCsubsetscirculating whomDCsareimpaired,DCsderivedfromtheperipheralblood intheperipheralbloodarereducedsubstantiallyinchronicHCV- of healthy individuals and patients who spontaneously cleared infectedpatients.39-41,47-50Indeed,thenumbersofcirculatingDCs HCV infection were phenotypically comparable and functionally correlate inversely with serum alanine aminotransferase levels and normal.42,66 the severity of liver disease in chronically infected patients.51 It is The mechanisms underlying DC dysfunction during HCV interesting to note, however, that while the numbers of mDCs infectionarenotfullyunderstood.Thecore,NS3,NS4andNS5 and pDCs in the peripheral blood decrease, there is a significant proteins impair DC function by diminishing the HLA and co- increasesinbothpopulationsfoundintheliversofchronic,HCV stimulatory molecule expression, reducing cytokine production, infected patients.50,52,53 Furthermore, the ratio of mDCs/pDCs is inhibiting TLR signaling, and decreasing allostimulatory activ- higher in the liver than the peripheral blood of these chronically ity.82 The HCV core protein induces IL-10/TNF-a secretion by infected patients suggesting preferential migration of mDCs to monocytes,whichtriggerspDCapoptosisand,indirectly,reduces areas of liver inflammation.51,52 This has led investigators to IFN-a secretion.49,83 Similarly, IL-10 produced by monocytes in speculate that active trafficking and intrahepatic compartmenta- response to core, NS3 and/or NS4 proteins impairs DC lization of DCs constitutes the principal mechanism responsible maturation, reduces allostimulatory activity, suppresses IL-12 for decreased circulating DCs in chronically infected production and, consequently, interferes with T polariza- h1 patients.42,50-52 While the mechanism(s) remains to be clarified, tion.72,77,84-86 immature DCs in the bloodstream express inflammatory Conflicting evidence, however, shows that DCs in chronic chemokine receptors, e.g., CCR5, and migrate to the liver in HCVinfectedpatientsareneitherfunctionallynorphenotypically response to HCV infection and the elevated production of impaired and exhibit normal activity.56,57,87 DCs in chronically chemokines,e.g.,RANTES,MIP-1aandMIP-1β.53,54Normally, infected patients express typical maturation markers and CD83, uponmaturationinhealthytissues,DCsdownregulateCCR5and CD86, CD54 and HLA-DR levels similar to those expressed by upregulate CCR7 expression enabling the cells to respond to the healthy patients.56,88 Additionally, DCs derived from healthy cognateCCR7chemokine(CCL21)andtraffictotheTcellsareas subjects and patients with chronic HCV infections demonstrate of lymphoid tissues.54,55 In sharp contrast to healthy individuals, comparableabilitiestoprimeallogeneicTcells.56,60,88Healthyand however, recent studies demonstrated the expression of CCR5, infected patients secrete similar quantities of IL-12 and but not CCR7, by pDCs and mDCs circulating in the blood of IFN-a.57-60 DCs derived from chronically-infected patients HCV-infected patients.42,52,55 Moreover, HCV E2 protein exhibited normal antigen uptake, peptide-MHC complex forma- rendered CCR7-expressing DCs unresponsive to CCL21.52 tion, and antigen trafficking suggesting that the capacity to Thus, the attenuated anti-viral response characteristic of chronic, present antigen is preserved during HCV infection.63 612 Virulence Volume3Issue7 A variety of factors contribute to these discrepant results can be mediated by multiple mechanisms although it is generally including: (1) the limited number of patients enrolled in studies; agreed that the effects of nT cells are primarily mediated by reg (2) patient related factors such as age, gender, co-infection and direct, cell-to-cell contact.105 alcohol use; (3) duration of infection, liver inflammation and Inhibitorycytokinesconstituteaprincipalcontact-independent disease progression; (4) tissue source of DCs analyzed (i.e., mechanism by which T cells suppress T cell activity (Fig.3). reg eff peripheralbloodvs.liver)and(5)whetherthedataoriginatefrom Solubleandmembrane-boundtransforminggrowfactor(TGF)-β, freshly isolated DCs or monocyte-derived DCs obtained from forexample,playacriticalrolebothininducingandmaintaining chronic HCV-infected patients.47 Indeed, given the paucity of nT and iT cells, and in blocking the activation of reg reg DCs in the bloodstream and the challenge of tissue acquisition, conventional T cell.103,106-108 Similarly, T cell-dependent eff reg most human studies are conducted with DCs generated in vitro production of interleukin 10 (IL-10), plays an important role in fromCD14+monocyteprecursorspresentintheperipheralblood. suppressing the responses of CD4+ T cells to a variety of eff The differentiation of monocyte-derived DCs in vitro resembles pathogens both used in animal models and implicated in human thedevelopmentofmDCsinvivo;notably,pDCsarenotreadily disease.93 expand or derive in vitro.71,89 Contact-independent mechanisms of T cell-mediated sup- reg pressionalsoinvolvetheconstitutive,high-levelexpressionofthe Regulatory T Cells IL-2receptor(CD25).T cellsarecapableofrelativelylittleIL- reg 2 production and, consequently, require IL-2 derived from an CD4+ regulatory T cells, characterized by the transcription exogenous source.109 As such, the rapid consumption of IL-2 by (reg) factor forkhead box P3 (FoxP3) and the constitutive, cell-surface T cells deprives T cell populations of IL-2 necessary for reg eff expression of the interleukin (IL)-2 receptor a chain (CD25), activation and proliferation.109 Cell surface nucleotidase activity represent one of the major mechanisms underlying immuno- (i.e., CD39 and CD73) constitutes an additional mechanism by logical self-tolerance and homeostasis.90 Mutations in FoxP3 and which T cells disrupt the metabolic activity of T cells.110 reg eff T cell dysregulation cause severe autoimmune disease and These ectonucleotidases rapidly degrade extracellular ATP reg immunopathologyleadingtodeathinbothmiceandhumans.91,92 released by activated or damage cells and abrogate the T cells also constitute an important factor in moderating proinflammatory response that would otherwise occur.110 In reg effectorimmuneresponsestopathogensthatcanpotentiallycause addition, adenosine generated as a product of ATP degradation serious organ and tissue damage to the host if left unabated.93 binds A2A receptors expressed by T cells and prevents effector Though critical for maintaining immune homeostasis, T cells cell activation.110-112 reg can also suppress effective immune responses to autologous T cells also exhibit the ability to suppress T cell function reg eff tumors, e.g., metastatic melanoma and hematological malignan- by a number of contact-dependent mechanisms. Both mouse cies, and contribute to the persistence of infections by a wide andhumanT cells,forexample,exhibitcytotoxicactivityand reg variety of human pathogens.93-95 the ability to induce apoptosis by T cells dependent upon eff TwotypesofT cellsarecommonlydescribedintheliterature granzyme A or B and perforin.108,113 Galectin-1, a member of a reg and classically distinguished bysite of origin: natural (n)T cells highly conserved family of β-galactosidase-binding proteins, has reg generatedbyhigh-avidityselectioninthethymus;andadaptiveor also been implicated in the immunosuppressive activity inducible (i)T cells derived from antigen-stimulated conven- exhibited by T cells.114 Galectin-1, expressed on the cell reg reg tional (CD4+CD25-FoxP3-) T cells in the periphery (Fig.2).96,97 surface, inhibits cell proliferation and promotes apoptosis by nT cells can induce “infectious tolerance” by converting activated T cells reg eff conventional T cells into iT cells directly by cytokine (IL-10, In addition to regulating T cell functions directly, T cells reg eff reg TGF-β or IL-35)-dependent mechanisms or -independent can suppress conventional T cell activity indirectly by inhibiting mechanisms mediated by contact with DCs.98,99 It has been DC maturation and immunostimulatory activity.108 In a process suggested that nT and iT cells express complementary, called trans-endocytosis, for example, cytotoxic T lymphocyte-4 reg reg immunefunctions,thatnT cellsandiT cellsarededicatedto (CTLA-4) molecules on the surface of T cells capture, reg reg reg preventingautoimmunityandtomaintaininganon-inflammatory internalize and degrade CD80 and CD86 expressed by DCs environment, respectively.96 Notably, there are no definitive rendering the latter tolerogenic and limited in their capacity to markers that identify T cells, or distinguish nT and iT sensitize naïve T cells.115 Similarly, lymphocyte activation reg reg reg eff subsets. While FoxP3 is a transcription factor common to both gene-3 (LAG-3 of CD223), a CD4 homolog that binds MHC subsets, it is also expressed transiently by activated, conventional classIImolecules,suppressesDC maturation andco-stimulatory human T cells that do not exhibit immunosuppressive activity.97 molecule expression.116,117 Neuropilin (Nrp-1), a molecule also Moreover, while CD25+ T cells isolated from naïve mice are expressed by T cells, promotes long-term T cell interaction reg reg almost exclusively nT cells; CD25 expression in humans is with immature DCs and, thus, inhibits immune recognition by reg much more heterogeneous.97 naïve CD4+ helper T cells.118 Notably, the suppressor functions Once activated, T cells are able to suppress the activity of a of T cells undoubtedly rely upon a combination of all the reg reg widerangeofimmunecelltypesincludingbothCD4+andCD8+ factorsdescribed.Moreover,itislikelythatoneormoreofthese Tcellsubsets,Bcells,NKcells,NKTcells,macrophagesandDCs factors affect both T cells and DCs, as well as other immune eff (a phenomenon called bystander suppression).100-105 Suppression cell types. www.landesbioscience.com Virulence 613 Figure2.FoxP3+T cellproductioninthethymusandperiphery.Natural(n)T cellsaregeneratedbyhigh-avidityselectioninthethymus.Inducible reg reg (i)T cellsderivefromantigen-stimulatednaïveTcellsintheperiphery.nT cellscanpromoteiT celldevelopmentbycytokine-dependent reg reg reg mechanisms(infectioustolerance). Contribution of T Cells to the Pathogenesis stimulation with HCV T regulatory epitopes.119,121,124 In one reg of Hepatitis C study, global gene expression analysis comparing FACS-sorted CD4+/CD25high T cells (nT phenotype) from HCV-infected reg T cells play a prominent role in the pathogenesis of chronic and uninfected individuals found only minimal differences reg HCV infection. This role was first suggested based upon the between the two populations.124 In contrast, other investigators increasedfrequencyofT cellsfoundintheliverandcirculating observed an increase in HCV antigen-specific T cells reg reg in the peripheral blood of chronically-infected patients compared phenotypically consistent with iT cells, which induced reg withuninfectedindividualsorpatientswhospontaneouslycleared suppression via induction of IL-10 or TGF-β.120,126 Regardless, the virus.23,24,93,119-123 Moreover, CD4+CD25+ T cells isolated the consensus seems to be that the expanded T cell population reg fromthebloodofHCV-infectedpatientssuppressedvirus-specific inchronicallyinfectedHCVpatientsisheterogeneous,composed CD8 T cell responses, while depletion of the CD25+ T cell ofbothnT andiT cellsubsets.Conceivably,theinitialHCV reg reg population enhancedtheproliferation ofcellsthatremained.23,123 epitope-specific response of nT cells to infection induces the reg Untilrecently,however,itremainedunclearwhetherthisincrease expansion of, and subsequent suppression by, iT cells (i.e., reg in T cells represented an HCV antigen-specific response or infectious tolerance).98 reg occurred as a nonspecific consequence of chronic inflammation TheresponseofnT cells,whichnormallyfunctiontosuppress reg and liver disease. Furthermore, descriptions in literature of the autoimmunity, suggests that HCV encodes peptide (epitope) phenotype and function of the T cell populations are not sequences homologous to self-antigen.119,128 Indeed, a BLAST reg consistent. searchoftheviralgenomeidentifiedanumberofT cell-epitopes reg HCV-encoded T cell epitopes have now been identified in published in the literature that exhibited extensive human reg both structural (i.e., core) and non-structural (NS3, NS4 and homology (Ardito and Losikoff, unpublished observation). While NS5b) proteins.119,120,124-127 Utilizing dye-conjugated, HCV these epitopes elicited a response by T cells circulating in the reg peptide-loaded MHC class II tetramers to stain the cell, bloodstreamofchronic,HCV-infectedpatients,theyfailedtoelicit Ebinuma and coworkers were the first to report HCV antigen- a similar responseby cellsobtainedfrom healthycontrols.119 This specific recognition by FoxP3+ T cells contained among the seems to imply that these HCV-specific nT cell populations reg reg PBMCs derived from chronically infected patients.124 A number expand in vivo during chronic disease.122,129 It is relevant to note, of studies have demonstrated an increase in the HCV-antigen therefore, that many published epitopes recognized by HCV- specific FoxP3+/CD25high cell population (phenotypically similar specificT cellsarelocatedadjacenttooroverlappingwithT cell reg eff tonT cellsexpressingananergiccytokineprofile)inresponseto epitopesassociatedwithviralclearance.119,124,130 reg 614 Virulence Volume3Issue7 Figure3.MechanismsmediatingT cellsuppression.FoxP3+T cellssuppressT cellactivity(A).T cellsinhibitT cellactivitybymultiplecontact- reg reg eff reg eff dependentand-independentmechanismsdescribedinthetext.FoxP3+T cellsimpairDCfunction(B).Similarly,T cellsimpairDCmaturationand reg reg functionbymechanismsdescribedinthetext. Several cross-sectional studies demonstrated a strong correla- patient ultimately cleared virus or developed chronic dis- tion between increased T cell numbers and chronic HCV ease.121,130 In one study, T cells derived from patients in reg reg infection.23,123,124 The specific role of T cells in viral whom viremia persisted exhibited significantly more suppressive reg persistence could not be determined, however, since the patients activity in vitro than did cells obtained from patients who were previously infected at some undetermined date. In this spontaneously cleared the virus.121 The authors concluded that regard, two longitudinal studies involving patients acutely maintaining an elevated T cell population regulated (sup- reg infected with HCV reported no difference in the frequency or pressed) the T cell response and promoted the development of eff function of circulating T cells irrespective of whether the chronicity. reg www.landesbioscience.com Virulence 615 Figure4.ImmunesuppressionmechanismsinHCVinfection.BoththenumberandfunctionsofcirculatingmDCsandpDCsarediminishedincasesof chronichepatitisC.ImmatureDCspromotetheexpansionandfunctionofFoxP3+T cells.T cells,inturn,suppressCD4+andCD8+Tcell,NKcell,NKT reg reg cell,Bcell,macrophageandDCactivities.Redandbluearrowsindicateactivationandsuppression,respectively. Recently, Cusick et al. reported that a variant of an inhibitory effect on the capacity of DCs derived from healthy immunodominant HCV epitope emerged during the course of individuals to express HLA and cell surface co-stimulatory persistent HCV infection.127 This epitope variant induced a molecules, synthesize proinflammatory cytokines such as IL-12 populationofFoxp3+CD4+T cellsthatwasabletosuppressthe and induce allogeneic T cell proliferation.82 These same viral reg responseofT cellstothecognate,butnotanunrelated,peptide. proteinsfailedtoaffectTcellproliferationdirectly,supportingthe eff Thus, variants of MHC class II-restricted epitopes arise as a contention that the effect of HCV on T cell function depends eff consequence of immune pressure to evade host defenses, and upon the intermediary role of DCs.82 Recent studies suggest, these variants induce epitope-specific T cells that attenuate however,thatbothDCsandconventionalT cellsaresusceptible reg eff conventionalCD4+Tcellhelprequiredtoclearvirusinfection.In to HCV infection.131-133 In the former case, the binding and cases of chronic disease, T cells suppress virus-specific CD4 T subsequent internalization of viral particles are mediated by the reg cell activity, impairing maintenance of T cell function and interaction of envelope glycoproteins E1 and E2 with dendritic eff promoting viral persistence. cell-specific C-type lectin (DC-SIGN), a cell surface receptor expressed by DCs.133 Consequently, the authors speculated that Impaired DCs, T Cells and the Pathogenesis even in the absence of a productive infection, HCV E1 and E2 reg of Chronic HCV bound to DC-SIGN might transmit a signal that promoted tolerance and T cell formation. In the case of CD4+ T cells, reg It is not entirely clear whether HCV affects the response of T Dominguez-Villar and coworkers reported that the Jurkat T cell reg cells to infection directly or indirectly, dependent upon the line transfected with an HCV core-expressing vector upregulated intermediary role of some other cell type. There is accumulating FoxP3andCTLA-4,andacquiredtheabilitytosuppressthenon- evidence to suggest, however, that DCs play a key role in the specificproliferativeresponseofboth CD4+andCD8+Tcells.134 expansion of T cells during chronic HCV infection. Indeed, This latter finding implies the potential capacity of HCV reg HCV proteins (core, NS3, NS4 and NS5) exert a marked, infection alone to induce T cells formation. reg 616 Virulence Volume3Issue7 While the virus may infect T cells and DCs directly, impaired Summary DC function appears to play a key role in the induction and maintenance of HCV-specific T cell responses. In this regard, DCs circulating in the peripheral blood of chronic, HCV- reg overwhelming evidence supports the role of DCs in establishing infected patients are functionally impaired. Both pDCs and andmaintainingimmunologicaltolerancetoforeign,aswellasself, mDCs are reduced in number and exhibit decreases in: cytokine antigens.135,136 In particular, the liver provides a prototypical production, cell-surface co-stimulatory molecule expression and/ tolerogenic environment in which interactions that include DCs orallostimulatoryactivity,resultinginaninabilitytoprimenaïve andT cellsfosterdevelopmentofchronicinfectiousdiseases,e.g., T cells and, consequently, a reduction in anti-viral activity reg eff viral hepatitis.137 While the underlying mechanisms remain to be (Fig.4). On the other hand, the number and function of T reg delineatedfully,itisgenerallyagreedthatimmatureDCspromote cells in thebloodofthese same patients areincreased correlating T cellfunction.135-139Itispertinenttonote,therefore,thatDCs with the development of persistent viral infection. T cells can reg reg purified from human liver tissue primarily express an immature, suppress the activity of other immune cell types including T eff myeloid phenotype characterized by the low-level or negligible cells directly by contact-dependent and -independent mechan- expressionofcell-surfaceco-stimulatorymolecules:CD40,CD80, isms, or indirectly by inhibiting DC maturation and immunos- CD83andCD86.137Moreover,comparedwithDCspurifiedfrom timulatory capacity. As such, recent studies indicate that peripheral blood, liver DCs produce significantly higher levels of immature DCs are a critical factor in the pathogenesis of IL-10 and lower proinflammatory cytokine (i.e., IL-1β, IL-6 and chronichepatitisCbyfailingtoinduceadequatelynaïveT cell eff TNF-a) levels following TLR4 ligation. Finally, compared with function and, conversely, promoting the development and DCs in the blood, liver DCs stimulated the IL-10-dependent activity of T cells. reg production of more CD4+CD25+FoxP3+ T cells in co-cultures reg that contained naïve, allogeneic CD4+ T cells.138 Similar results were found when allogeneic T cells were co-cultured with mDCs obtained from healthy control and chronic, HCV-infected Acknowledgments patients.79 Relative to the controls, mDCs derived from infected Support was provided by National Institutes of Health Research patientsstimulatedamarkedexpansionofT cells. Grant U19 AI082642. reg References 9. 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