Lymphotoxin in physiology of lymphoid tissues – Implication for antiviral defense

Cytokine xxx (2016) xxx–xxx

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Lymphotoxin in physiology of lymphoid tissues – Implication for antiviral defense Ekaterina P. Koroleva a, Yang-Xin Fu b, Alexei V. Tumanov a,⇑ a b

Department of Microbiology, Immunology, and Molecular Genetics, University of Texas School of Medicine, UT Health Science Center, San Antonio, TX, USA Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX, USA

a r t i c l e

i n f o

Article history: Received 2 June 2016 Received in revised form 17 August 2016 Accepted 19 August 2016 Available online xxxx Keywords: Lymphotoxin Lymphotoxin beta receptor Antiviral immunity Lymphoid organs Type I interferon

a b s t r a c t Lymphotoxin (LT) is a member of the tumor necrosis factor (TNF) superfamily of cytokines which serves multiple functions, including the control of lymphoid organ development and maintenance, as well as regulation of inflammation and autoimmunity. Although the role of LT in organogenesis and maintenance of lymphoid organs is well established, the contribution of LT pathway to homeostasis of lymphoid organs during the immune response to pathogens is less understood. In this review, we highlight recent advances on the role of LT pathway in antiviral immune responses. We discuss the role of LT signaling in lymphoid organ integrity, type I IFN production and regulation of protection and immunopathology during viral infections. We further discuss the potential of therapeutic targeting LT pathway for controlling immunopathology and antiviral protection. Ó 2016 Elsevier Ltd. All rights reserved.

1. Introduction Lymphotoxin-alpha (LTa, TNFSF1), soluble homotrimeric cytokine, is a member of tumor necrosis factor (TNF) superfamily and was originally identified as a product of lymphocytes that was capable of exerting cytotoxic effects on tumor cells in vitro (for a recent review see [1,2]). LTa3 homotrimer binds to TNF receptor 1 (TNFRSF1A) and TNF receptor 2 (TNFRSF1B) with high affinity, but it has less activity in driving TNFR signaling than TNF itself. LTa forms a heterotrimer with LTb (TNFSF3), and this membrane-bound heterotrimer signals specifically through LTbR (TNFRSF3) [3,4]. Surface LT is expressed by B and T lymphocytes, natural killer cells, innate lymphoid cells (ILCs), and dendritic cells (DCs), whereas LTbR is mainly expressed by non-lymphocyte populations, such as epithelial cells, stromal cells, DCs and macrophages [3,5,6]. Therefore, this cytokine-receptor pair interaction serves as a bridge between lymphoid cells and non-lymphoid cells, including stromal and parenchymal cells. LIGHT (TNFSF14) is another LTbR ligand that is predominantly expressed by T cells, DCs, and macrophages [3,4,7]. Genetic disruption of LT signaling in mice results in a complex phenotype. Mice with inactivated lta, ltb or ltbr genes lack lymph nodes (LN) and Peyer’s patches (PP) and display disrupted microarchitecture of the spleen, thymus and other lymphoid organs (for a ⇑ Corresponding author. E-mail address: [email protected] (A.V. Tumanov).

review see [8,9]). Due to defects in lymphoid organ development and maintenance these mice display multiple immune abnormalities and impaired immune response to various infections (for a review see [10]). Lymphoid organ defects associated with the lack of components of LT signaling in mouse models are summarized in Table 1. Although the role of LT in lymphoid organogenesis is well defined, the contribution of LT pathway to homeostasis of lymphoid organs during the immune response to viruses is less understood and is the focus of this review.

2. Lymphotoxin signaling promotes lymphoid organ integrity for antiviral protection The principle function of secondary lymphoid organs (SLO) is to provide microenvironment for interaction between antigenpresenting cells and rare pathogen-specific lymphocytes for the induction of an efficient antiviral immune response (for reviews see [33–35]). SLO also reduce virus spreading by strategically localized cells producing various immune mediators, such as type I interferons (IFNs). Finally, SLO provide the necessary factors for the survival and differentiation of lymphocytes. Since the discovery that mice with genetic inactivation of LT or LTbR bear major defects in the development and structure of lymphoid organs (for review see [3,8,27], and Table 1) these mice become an irreplaceable animal model to study antiviral immune responses. Growing numbers of papers demonstrating unique requirement for LT signaling in antiviral immunity will be discussed in this chapter.

http://dx.doi.org/10.1016/j.cyto.2016.08.018 1043-4666/Ó 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: E.P. Koroleva et al., Lymphotoxin in physiology of lymphoid tissues – Implication for antiviral defense, Cytokine (2016), http://dx.doi.org/10.1016/j.cyto.2016.08.018

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E.P. Koroleva et al. / Cytokine xxx (2016) xxx–xxx

Table 1 Mice with specific inactivation of components of LT pathway demonstrate defects in lymphoid organ development and structure. Mutant strains

Spleen B cell follicles

Lta / Ltb / Ltbr / Light / B-Ltb / T-Ltb / B,T-Ltb / RORct-Ltb RORct-Lta VE-Ltbr / Ccl19-Ltbr Tagln-Ltbr

+

/ /

/ /

LN MZM, MMM

FDC

+

+

+ +/ +

+ + ND + +

+ + ND + +

+ + ND + +

GALT

Structure

mLN

pLN

Abnormal

+/

+ Abnormal + Abnormal +

+ +

+ +

+ +

Abnormal Abnormal +

+ + +

PP

NALT

Thymus

References

+/ +/ +/ ND ND ND ND ND ND ND ND ND

Abnormal Abnormal Abnormal Normal ND ND ND ND ND ND ND ND

[11–16] [14,16–18] [13,16,19–22] [23] [24–26] [24,26] [26,27] [6,28] [28] [29] [30,31] [32]

ILF

+

+ +/ + +/

+ + + +

+/ + +

+/ + ND

ND + ND

pLN-peripheral lymph node, mLN-mesenteric lymph node, PP-Peyer’s patches, NALT-nasal-associated lymphoid tissue, FDC-follicular dendritic cells, MZM-marginal zone macrophages, MMM-metallophilic macrophages, ND-not determined, absent, + present, +/ reduced.

The specific outcomes of viral infections in mice deficient with components of LT signaling pathway are summarized in Table 2. Several studies which utilized LTa-, LTb- or LTbR-deficient mice demonstrated that overall antiviral cytotoxic T-cell immune responses were impaired, and the clearance of the virus was slowed down or inhibited in various models of systemic viral infections, such as vaccinia virus [36], lymphocytic choriomeningitis virus (LCMV) [36–38], herpes simplex virus (HSV) [39] or Theiler’s

murine encephalomyelitis virus (TVEM) [40]. Adoptive transfer experiments demonstrated that LT-deficient environment rather than LT-deficient splenocytes is responsible for aberrant early replication of LCMV in the spleen and defective antiviral immune responses [38,41] Similarly, since treatment with LTbR-Ig did not impair immunity against TVEM in adult mice [40], it was suggested that changes to the splenic and lymph node architecture, but not the LT signaling during infection, were critical for clearing the

Table 2 Role of LT signaling in animal models of viral infections. Virus

Model

Outcome

Ref

Vaccinia LCMV LCMV LCMV LCMV LCMV LCMV

Tnf.Lta / Tnf.Lta / Ltb / Lta / , Tnf.Lta / Lta / Ltb / , B-Ltb / , T-Ltb / , TB-Ltb / LTbR-Ig treatment of WT mice, transfer of LTb-deficient B-cells B-Ltb / , Ltbr /

Attenuated primary CTL responses Reduced primary and secondary CTL responses Severely diminished CTL responses, delayed clearance of the virus Impaired initial virus replication in the spleen Impaired CD8+ T-cell responses, impaired clearance of the virus Delayed virus clearance in TB-LTb mice, persistent infection in LTb LTb on B-cells promotes LCMV-induced pLN remodeling

[36] [36] [37] [41] [38] [26] [71]

LCMV LCMV-13 MHV-68 MHV-A59 TMEV MCMV MCMV MCMV VSV VSV VSV VSV HSV HSV Influenza virus A (H1N1) Influenza virus A (H3N2) HCV HBV Rotavirus SIV

LTbR-Ig treatment of NZB mice Lta / Ccl19-Ltbr / Lta / , Ltbr / , LTbR-Ig treatment in C57Bl6 mice Lta / , LTbR-Fc transgenic mice Lta / , Ltb / , Ltbr / , LTbR-Fc; anti-LTbR agonistic treatment of Lta / mice Ltbr.Rag / Ltb.Light / , B-Ltb / Ltb / , B-Ltb / , T-Ltb / , TB-Ltb / Ltbr / LTbR-Ig treatment, BM transfer from B-Ltb / to WT mice B-Ltb / Lta / LTbR-Ig-treated Rag1 / mice Lta / , SLP mice (splenectomized Lta / mice reconstituted with BM from WT mice) Tnf.Lta

/

FL-N/35 HCV transgenic mice Agonistic anti-LTbR antibody to HBVtransgenic mice Lta / Ltbr / > WT BM transfer Rhesus macaques sooty mangabeys

/

mice

Impaired IFN-I production due to insufficient early virus replication but normal CD8+ Tcell responses Increased mice survival, reduced specific CD8+ T-cell responses Slightly delayed virus clearance Increased body weight loss and viral titers Increased mortality, impaired virus-specific CTLs, reduced demyelination. LTbR-Ig treatment failed to increase susceptibility. Increased susceptibility, accelerated mortality Increased mortality, impaired IFN-b induction Induction of IFN-b, increased survival of mice Reduced early IFN-I responses in spleen /

LTb mice succumb to infection. Reduced virus capture in MZ of B-LTb mice Decreased early virus titers in the spleen, impaired CD8+ T-cell responses, increased mortality Increased mortality after s.c. infection due to inability to replicate virus in SCS macrophages to produce IFN-I, leading to fatal invasion of intranodal nerves Reduced IFN-I production early after infection, reduced virus-neutralizing antibodies Increased susceptibility to virus-induced encephalitis, defective CD8+ T-cell responses Delayed development of lesions and increased survival Increased susceptibility of LTa / mice to infection, delayed, but effective primary and memory CD8+ T-cell and antibody responses. Increased resistance of SLP mice to infection compared to WT mice. TNF and LTa promote loss of bone marrow derived B cells during infection

[72] [117] [100] [30] [40] [52] [54] [55] [26] [59] [25] [61] [39] [44] [103,105,106]

[120]

Increased LTb expression in tumors of HCV-transgenic mice Reduced viremia and HBV core protein expression in the liver

[95] [80]

Delayed IgA production and clearance of intestinal virus Normal viral clearance, increased numbers of IFN-c producing T cells in intestine Loss of FRCs and IL-7 in lymph nodes correlated with decreased numbers of LTb expressing CD4+ T cells

[121] [122] [123,124]

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infection. It is important to note that LT deficient mice demonstrated reduced demyelination in the spinal cord after TVEM infection, compared to susceptible SJL mice [40], and LTb expression was induced in the brain following TVEM infection [42], suggesting that LT signaling is critical not only for mediating resistance to TVEM, but also for promoting demyelination. In line with these results, recent study demonstrated that Th17 cells by producing LT induced tertiary lymphoid tissue formation and remodeling of LTbR-expressing meningeal-resident stroma thereby promoting demyelination and CNS pathology in mouse model of EAE [43]. Recent study on immunocompromised mice revealed unexpected and intriguing role for the innate LT signaling in HSV infection [44]. LT signaling has been shown to play a key role in immunity against HSV [39]. Although HSV-1 specific IgG responses were impaired in Lta / mice immunized with UV-inactivated virus, and Lta / mice had impaired HSV-1 specific T cell effector functions and failed to control viral infection of the central nervous system [39], Rag1 / mice (lacking T and B cells) treated with LTbRIg to block LT/LIGHT signaling showed increased resistance to HSV1 infection: delayed development of lesions and increased survival, reduced late proinflammatory cytokine release in the serum and nervous tissue, and inhibited chemokine expression and inflammatory cell infiltration in the dorsal root ganglia [44]. Thus, the role of LT signaling in antiviral immunity in immunocompromised host should be an important aspect of future studies. Recent studies revealed marked disruption of secondary lymphoid organs is chronic HIV and SIV infections [45–48]. Interestingly, disruption of fibroblastic reticular cell (FRC) network was associated with reduced expression of homeostatic CCL21 chemokine, IL-7, and LTb [49]. Inactivation of LTbR in FRC in mice resulted in impaired homeostatic chemokine and interleukin-7 expression in lymph nodes [101]. IL-7 is produced by FRC and is required for survival of T cells [50]. Thus, LTbR signaling in FRC may promote the function of FRC and production of IL-7, which may have an impact on T cell survival and function during HIV infection. Therefore, LTbR agonists may have therapeutic potential to restore the structure of lymphoid tissues to ameliorate the severity of the disease.

3. Lymphotoxin-dependent regulation of type I Interferons in viral infections Accumulating evidence suggests that LT plays an important role in the regulation of type I interferon (IFN-I) responses (for a recent review see [51]). Studies using human cytomegalovirus (HCMV) revealed the first link between LT signaling pathway and the induction of IFN-I [52]. Herpesviruses cause little or no pathogenicity in immunocompetent host, but establish lifelong persistence with latency. Signaling mediated by LTbR activated NF-kBdependent transcription of IFN-b in HCMV-infected fibroblasts, blocking HCMV viral spread through the monolayer [52,53], although IFN-b dependent arrest of virion production and virus spread did not lead to the elimination of virus from infected cells [53]. Studies using in vivo models of mouse CMV infection (MCMV) reinforced the importance of LT system in the induction of the initial wave of IFN-I [52,54,55]. Lta / mice were profoundly susceptible to lethal infection with MCMV requiring 100-fold less virus that WT controls [52]. Although Lta / mice display multiple defects in lymphoid organs, which could account for their susceptibility to MCMV, mice expressing LTbR-Fc decoy as a transgene, which have normal lymph node development, were also susceptible to MCMV, indicating that developmental abnormalities were not likely to be responsible for increased susceptibility of Lta / mice to MCMV infection [52]. Follow up studies revealed that

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induction of IFN-b was severely impaired in MCMV-infected Lta / mice, but immunotherapy with agonistic anti-LTbR ab restored IFN-b levels and enhanced survival of mice [54]. Following intraperitoneal infection, MCMV was captured in the splenic marginal sinus within six hours after infection, infecting CCL21-expressing LTbR-dependent stromal cells, and spreading to the red pulp by 17 h post infection [56,57]. MCMV infection induced biphasic type I IFN response in the spleen, with initial peak of IFN-I expression at 8 h post infection, paralleled with the rise of serum IFN-a, and declined over the next 16 h. A second, more sustained accumulation of IFN-a and -b occurred between 36 and 72 h and lasted for a few days [55]. It was demonstrated that B-cell expression of LTb and expression of LTbR on stromal cells are the key factors for promoting the initial IFNab response in the spleen independently of TLR signaling [55]. In contrast, LTbR signaling in DCs produced IFN-b at levels reflecting homeostasis [58]. Thus, communication between LT-expressing B cells and LTbR responding stromal cells initiated the earliest IFN-I response to MCMV. Another example of virus infection utilizing type I IFNdependent defense mechanism in concert with LT provided by B cells is cytopathic vesicular stomatitis virus (VSV). Mice deficient in LTb expression in T-cells (T-Ltb / ), B-cells (B-Ltb / ), T and Bcells (TB-Ltb / ) and mice with complete deficiency of ltb gene (Ltb / ) were used to investigate how the integrity of secondary lymphoid organs affects the protective immunity to systemic VSV infection. All LTb-deficient mouse strains mounted early and strong virus neutralizing IgM titers following systemic infection with VSV, however Ltb / mice died between days 8–11 following infection [26]. Immunization with non-replicating UV-inactivated VSV led to reduced IgM and IgG titers in all LTb-deficient strains, indicating that highly organized lymphoid structure was dispensable for the generation of neutralizing antibody responses against live VSV, but critical for the induction of B-cell responses against non-replicating antigens [26]. After VSV infection, virions are rapidly captured within the MZ. B-Ltb / and TB-Ltb / mice showed a partial, and Ltb / mice showed a complete impairment of VSV capture in MZ, allowing uncontrolled virus spread to neuronal tissue, leading to mouse death [26]. Metallophilic macrophages in the marginal zone (recognized by MOMA-1/Siglec1/ CD169 antibody) capture VSV virions, present captured virus antigen and can produce type I IFN. The expression of the protein ubiquitin-specific peptidase Usp 18, an inhibitor of IFNR signaling, in metallophilic macrophages led to lower type I IFN responsiveness, allowing locally restricted replication of virus and sufficient antigen production, which is required for the induction of adaptive antiviral immune responses [59,60]. VSV glycoprotein expression was impaired in the spleen of Ltbr / mice, which correlated with the low number of CD169+ macrophages in these mice. Accordingly, early viral titers in the spleen were much lower in Ltbr / mice, suggesting that LTbR signaling is involved in the process of viral replication [59]. In line with this work, recent study by Xu et al. demonstrated that BAFFR-deficient mice had lower LT expression in the spleen which was insufficient to induce type I IFN and maintain normal levels of CD169+ cells thereby leading to death after systemic VSV infection [61]. Consistently, B-Ltb / mice infected intravenously with VSV exhibited fewer CD169+ cells, had reduced type I IFN production shortly after infection and low-dose infection of these mice resulted in reduced production of neutralizing antibodies [61]. In contrast to systemic VSV infection, when VSV was administered subcutaneously (s.c.), survival of mice was independent of neutralizing antibody production or cell-mediated adaptive immunity. Instead, LT production by B-cells was required to maintain a protective subcapsular sinus (SCS) CD169+ macrophage phenotype within virus draining lymph nodes. SCS macrophages that are deprived of B-cell-produced membrane LT can still capture

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lymph-born VSV but fail to replicate it. Without replication, SCS macrophages were not capable to produce IFN-I which was required to prevent VSV invasion of intranodal nerves [25]. Since SCS macrophages in LNs contribute to protection against secondary bacterial infections [62], it will be important to define the role of B cell-derived LT in the maintenance of SCS macrophages in protection against secondary bacterial infections in future studies. During the persistent virus infection type I IFN and CD8+ T-cells control virus replication in infected cells. CD8+ T-cells are activated early by viral replication, but prolonged viral replication results in T-cell exhaustion and persistence of virus [63,64]. The induction of IFN-b is crucial for protective CD8+ T-cell responses to LCMV [65]. Studies utilizing LCMV virus infection model shed a light into connection between LT signaling, IFN-I induction and CD8+ T-cell responses. Generation of antiviral cytotoxic T cell lymphocyte (CTL) responses following LCMV infection correlated well with the increasing disorganization of lymphoid structure in B- and Tcell specific LT deficient mice, however only Ltb / mice were not able to eliminate the virus from spleen by day 30 post infection [26]. Declining numbers of LCMV-infected DCs were detected in Ltb / mice, where no CTL priming was observed [26]. LCMV replicated inefficiently in splenic DCs of Ltb / mice, likely causing impaired CTL priming, uncontrolled virus spread and CTL exhaustion, suggesting that LT-dependent integrity of DCs network is key for the outcome of the virus-specific CTL response [26]. In line with these studies, Summers DeLuca et al. highlighted the role of LT in the regulation of CD8+ T-cell homeostasis by inducing the expression of IFN-I by DCs in response to a model antigen using OTI/OTII transgenic system [58]. Interestingly, DCs can express both LTbR and LTbR ligands, suggesting potential homotypic DCs interactions. In fact, intrinsic LTbR signaling in DCs has been shown to regulate proliferation and survival of DCs [66,67]. On the other side, crosstalk between LT expressing DCs with LTbR responding stromal cells is required for the maintenance of stromal compartments in secondary lymphoid organs [68,69]. Production of LT by B cells has been also shown to promote restoration of T cell stromal compartments and B cell follicles, disrupted during LCMV or helminth infection [31,70,71]. Inactivation of LTbR in FRCs resulted in impaired CD8+ T cell activation and reduced clearance of LCMV [30]. Thus, both B cells and DCs can be source of LT for maintaining the integrity of lymphoid organs during the immune response to viral and bacterial infections. Further, a recent study by Shaabani et al. focused on the role of LT in induction of type I IFN and CD8+ T cell responses in LCMV infection revealed that LT can regulate IFN-I induction independently of CD8+ T-cell activity [72]. During systemic LCMV infection virus spreads along the conduits of the marginal zone. Infected BLtb / mice demonstrated several spots of infected cells in the spleen, but no distribution along the marginal zone [72]. In contrast to Usp18-deficient bone marrow-derived macrophages, LTbR-deficient macrophages did not display reduced viral replication in vitro, despite limited replication in vivo in spleens of Ltbr / mice. This decreased viral replication in vivo was not caused by the reduction of CD169+ macrophages because depletion of CD169+ macrophages in CD169-DTR mice did not reduce viral replication in the spleen [72]. B-cell derived LT was essential for viral replication since B-Ltb / mice displayed reduced viral titers in the spleen [72]. IFN-I production was dependent on early virus replication in the spleen and was strongly impaired in both Usp18 / and BLtb / mice. However, despite impaired IFN-I production in both Usp18 / and B-Ltb / mice, CD8 + T cell responses were limited only in Usp18 / but not in B-Ltb / mice. Infection of these mice with single-cycle virus (rLCMV), which can replicate in infected cell but cannot produce infectious virus particles, failed to induce IFN-I, but was still capable to induce CD8+ T cells responses suggesting that spread of the virus is essential for inducing IFN-I, but not for

expansion of virus-specific CD8+ T-cells [72]. Thus, although LCMV replication is sufficient for CD8+ T-cell activation, both virus replication and extracellular virus spreading (controlled by LT) are necessary for inducing systemic IFN-I. In summary, these two mechanisms of virus propagation can influence the outcome of viral infection, since various infections could regulate both mechanisms separately. Although the exact mechanism by which B cell derived LT regulates extracellular virus spreading and induction of type I IFN remains to be determined, regulation of integrity of the marginal zone and SCS in the lymph nodes by B cell-LT is one possibility (Fig. 1 and [24,27,34,71]).

4. Role of LT in HBV and HCV infections Chronic liver diseases such as hepatitis B (HBV) and C (HCV) virus infections are associated with hepatocellular necrosis, continual inflammation and hepatic fibrosis, which may progress to cirrhosis and hepatocellular carcinoma (HCC) [73–75]. Therefore, effective antiviral agents are urgently needed to delay or prevent progression from chronic hepatitis to cirrhosis and HCC. Despite the dramatic improvement of the long-term outcomes for patients with chronic HBV infection, the clearance of Hepatitis B surface antigen (HBsAg) is only achieved in a small portion of HBV patients (for the recent review in HBV therapy see [76]). HBV establishes a stable nuclear covalently closed circular DNA (cccDNA), which serves as the template for viral transcription and secures HBV persistence and is responsible for viral relapse after cessation of antiviral therapy [77,78]. Persistence of cccDNA is the major barrier to eradicating chronic HBV infection [79]. Recent study by Lucifora et al. reported that LTbR agonists stimulated non-cytolytic clearance of cccDNA [80]. Using HBV-infected, differentiated cell line dHepaRG, authors showed that activation of LTbR decreased levels of all HBV markers, including cccDNA. LTbR activation upregulated expression of APOBEC3 cytidine deaminases in HBVinfected cells, leading to deamination and subsequent degradation of cccDNA. Furthermore, activation of the murine LTbR in vivo by systemic application of an agonistic antibody reduced HBV viremia, HBV RNA and HBV core protein expression in the liver of HBV-transgenic mice [80]. Despite the fact that transient stimulation of LTbR led to the reduction of HBV viremia in HBV-transgenic mice [80], there is evidence that chronic activation of LTbR signaling when LT is expressed as a transgene under albumin promoter in the liver, can promote inflammation and HCC development [81]. Therefore, the timing of LTbR stimulation is very important for the development of potential therapeutic approaches targeting HBV. LTb levels are increased in various animal chronic liver injury models including bile duct ligation and choline-deficient, ethionine-supplemented diet models suggesting that increased LT expression may participate in repair processes, such as cell proliferation after injury [82–85]. In fact, LTbR signaling was found to be critical for hepatocyte proliferation and liver regeneration after partial hepatectomy in mice [86–88]. Furthermore, transient stimulation of LTbR signaling with an agonistic antibody promoted liver regeneration [86]. However, the exact molecular mechanism of LTbR-dependent regulation of liver regeneration remains to be determined in future studies. HCV infection is also associated with increased hepatic LT expression in vivo and in vitro and correlates with the severity of fibrosis in chronic HCV infection in humans [81,89]. Accumulating evidence suggest that HCV replication depends on components of the LTbR pathway [90] and HCV core protein can interact with the cytoplasmic domain of LTbR, stimulating the NFkB pathway [91–93]. FL-N/35 transgenic mice have a hepatocyte-targeted expression of the entire reading frame of the genotype 1b HCV.

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B-Ltb-/-

WT MZM

CD169 MAdCAM-1 SIGNR1 B220

FDC MMM

B cell follicle

MS Fig. 1. B cell-LT is critical for maintaining integrity of the marginal zone. Frozen spleen sections from naïve WT and mice with deficiency of surface LT on B cells (B-Ltb / ) were stained with indicated antibodies. Note the disruption of the marginal zone and B cell follicles, reduction of CD169+ and SIGNR1+ macrophages, and marginal sinus disruption (MAdCAM-1).

In this model, HCV protein expression renders male mice at risk for liver tumorigenesis after one year of age [94]. LTb expression was dramatically increased in all FL-N/35 tumors. LTa expression was also increased in tumors, but to a lesser extent, while LTbR levels did not differ significantly between tumoral and peritumoral samples [95]. Increased LTb expression in HCV-linked tumors lead to activation of NF-kB and proinflammatory signaling pathways. Using Huh7 cells expressing individual HCV proteins, it has been demonstrated that enzymatic activity of viral RNA-dependent RNA polymerase NS5B was required for increased LTb expression and for activation of both the canonical and the alternative NFkB signaling [95]. Thus, LTbR activation might not initiate tumorigenesis but rather contributes to tumor progression in this animal model [95]. The ability of LTbR signaling to induce various chemokines may also promote formation of tertiary lymphoid tissues and inflammation in the liver, which may increase the risk of developing cancer (for a review see [96,97]). Recent study showed that formation of ectopic lymphoid-like structures in the liver promoted HCC development which was dependent on LTbR signaling since LTbR–Ig treatment reduced HCC burden in mice expressing constitutively active IKKb in hepatocytes [98]. Additionally, another recent study revealed that metabolic activation of intrahepatic CD8+ T cells and NKT cells promoted nonalcoholic steatohepatitis (NASH) and liver cancer via cross-talk with hepatocytes. Liver-specific inactivation of LTbR and IKKb led to reduced HCC incidence, suggesting that these pathways regulate transition from NASH to HCC development [99]. These effects were dependent on LIGHT (TNFSF14) signaling as LIGHT-deficient mice showed reduced steatosis and incidence of HCC [99], consistent with the role of LIGHT in liver regeneration [87]. The role of surface LT in HCC development in this model remains to be determined. In summary, although the transient activation of LT signaling in the liver can be beneficial to clear persistent viral infection, sustained activation of LT pathway during chronic liver disease can lead to tumorigenesis. Thus, the timing of therapeutic application of LTbR agonists in combination with other antivirals, must be carefully evaluated.

5. Role of LT in respiratory virus infections Lymphotoxin signaling plays pleiotropic functions in lymphoid organ development and maintenance, lymph node remodeling, induction of type I IFN and T cell responses during systemic viral infections. Here we will describe the role of LT in in the regulation of local antiviral immunity in the lung.

Despite the strong role for LT signaling in controlling systemic viral infections, initial experiments with lung-tropic viruses did not reveal strong phenotype in mice with disrupted LT signaling. Lta / mice challenged intranasally with murine gammaherpesvirus 68 (MHV-68) were able to clear productive MHV-68 infection in the lung, although with slightly delayed kinetics, and efficiently controlled latent infection [100]. Surprisingly, infected Lta / mice failed to develop splenomegaly or lymphocytosis, characteristics of MHV-68 infection, instead, inflammatory infiltrates in the lungs of Lta / were described. Serum IgG levels were comparable between WT and Lta / mice, suggesting that despite the absence of germinal centers, class switching still occurred in Lta / mice [100]. Influenza represents one of major respiratory viral infections which cause severe lung pathology and remain a serious public health threat [101,102]. Studies using influenza virus infection demonstrated that LTa-deficient mice, which have impaired LT signaling via both LTbR and TNFRs, generated efficient, although delayed, protective T and B cell responses [103]. Unexpectedly, Lta / mice were able to generate protective immunity to influenza virus despite absence of lymph nodes and disruption of spleen architecture, suggesting that local immune responses in the lung of Lta / mice were sufficient for generation of protective immunity. LIGHT signaling does not appear to contribute for protection against influenza virus since LIGHT-deficient mice were capable of generating protective immune responses [104]. Furthermore, SLO were not necessary for generation of memory CD8+ T cell and antibody responses since splenectomized Lta / mice reconstituted with bone marrow (BM) cells from WT mice (SLP mice) and thus lacking all SLO were capable to generate primary and memory antiviral responses [105,106]. How were protective immune responses initiated in SLP mice in the absence of secondary lymphoid organs? A potential explanation is that tertiary lymphoid organs in the lung can substitute the function of secondary lymphoid organs during viral infection in induction of protective responses. iBALT, a tertiary lymphoid tissue (TLO) in the lung, which is formed during infection, can contribute to protection [107]. The role of TLO in lung homeostasis is controversial since they can serve as inductive sites for protective immunity but also contribute to immunopathology [108,109]. It has been shown that both Lta / and SLP mice were able to generate iBALT in the lung, although iBALT was less organized in Lta / mice [106]. Although LT is not required for formation of iBALT, it is required for the maintenance of the microarchitecture of iBALT. Transient inhibition of LTbR signaling

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with LTbR-Ig reagent during influenza infection reduced the expression of CXCL13 and CCL21 chemokines in the lung, reduced germinal centers and disrupted the iBALT structure [110]. Bone marrow transfer and DC depletion experiments suggested that LT producing DCs contributed to the maintenance of iBALT [110]. Further studies revealed that IL-17 produced by CD4+ T cells is essential for the formation of iBALT [111]. IL-17 acted by promoting LTaindependent expression of CXCL13, which is important for follicle formation [111]. Additional evidence that iBALT can participate in protection against influenza infection was supported by administration of iBALT inducing agents. iBALT-like lymphoid aggregates induced asymptomatically without infection using protein cage nanoparticles enhanced protection against primary influenza virus infection, characterized by accelerated virus clearance and reduced morbidity [112]. Therefore, approaches that cause the formation of iBALT may provide a therapeutic potential for broad spectrum viral protection in the lung. iBALT can replace the function of the spleen and other secondary lymphoid tissues in primary adaptive immune responses and also support the maintenance and re-expansion of adaptive immune memory responses following influenza virus infection. Although Lta / mice were capable to generate protective responses to influenza virus [103], the contribution of LT signaling for protection and immunopathology remains controversial, because Lta / mice have pre-existing iBALT-like lymphoid aggregates in their lung, which might be partially responsible for relative protection against MHV-68 or influenza virus infections. Inflammatory infiltrates containing areas of B and T cells were found in the lungs of naïve Lta / , Ltb / , and Ltbr / mice [12,17,19]. Interestingly, SLP and splenectomized Lta / mice lacking SLO, were significantly more resistant to influenza virus infection [105] indicating that LT signaling and TLO might also contribute to immunopathology during influenza infection. Future studies using mice with cell-specific inactivation of components of LT-LTbR signaling in the lung which do not have defects in development of secondary lymphoid organs and spontaneous lymphoid infiltrates in the lung will help to better define the role of this pathway in antiviral protection and lung immunopathology during respiratory viral infections. Lung pathology is a significant cause of the morbidity and mortality associated with acute respiratory virus infections. Destruction of the lung integrity following pulmonary viral infections could be due to both virus replication and host-generated inflammation associated with the recruitment of immune responses. During influenza infection, immune mechanisms are employed to destroy and remove infected cells in an attempt to clear the virus. While some of these events are required to clear the infection, they can also induce severe pulmonary immunopathology (for a recent review see [113,114]). Therefore, understanding the mechanisms regulating the balance between protection and immunopathology is critical for development of potential therapeutic approaches. Considering the ability of LTbR signaling to promote the expression of various chemokines and inflammatory mediators, including type I IFN, excessive activation of LTbR signaling may also contribute to lung immunopathology during respiratory virus infections. In fact, recent studies indicate that LIGHT signaling can contribute to lung immunopathology by promoting thymic stromal lymphopoietinmediated fibrosis and expression of inflammatory mediators [115,116]. Treatment of human lung epithelial cells with recombinant LT induced expression of ICAM-I and VCAM-I as well as promoted the secretion of inflammatory mediators, including GMCSF, CCL5, MMP-9 and IL-6, generating a specific inflammatory signature in lung epithelial cells [115]. Thus, signaling through LTbR constitutively expressed by lung epithelial cells may participate

in airways remodeling during inflammation and can be pathogenic during respiratory infections. Another evidence of pathogenic role of LT signaling in lung disease was reported using infection with LCMV clone 13. LCMV-13 can cause lethal disease in autoimmune prone New Zealand Black (NZB) mice, characterized by pulmonary failure. Unexpectedly, blockade of LTbR pathway in these mice using LTbR-Ig enhanced survival of infected mice. Moreover, LTbR-Ig treatment did not prevent elimination of the virus, but reversed respiratory pathology [117]. Persistent LCMV infection and influenza infection are linked with excessive pathogenic production of type I IFN which can induce cytokine storm and thereby promote lung immunopathology [64,118,119]. Considering the ability of LTbR signaling to induce type I IFN [51,52], it will be important to define whether pathogenic LT signaling in the lung can be attributed to type I IFN production. Thus, understanding the balance between protective functions of LTbR signaling in the lung by maintaining the integrity of iBALT and induction of inflammation is critical for potential therapeutic targeting of this pathway in respiratory diseases. 6. Concluding remarks LT is a potent cytokine with multiple functions, including the control of lymphoid organ development and maintenance, and the regulation of inflammation and autoimmunity. Therefore, targeting of LT cytokine pathway represents an exciting therapeutic potential for autoimmune and infectious diseases. LT is required for viral clearance by controlling the integrity of lymphoid organs, viral replication pathways and production of type I IFN. On the other hand, sustained LT signaling during chronic diseases may promote inflammation and autoimmunity. Therefore, future studies focused on precise timing and tissue-specific targeting of LT pathway will be important for development of novel immunotherapeutic strategies to ensure virus clearance and avoid immunopathology. Acknowledgements This work was supported by the National Institutes of Health (1R21AI111000 to A.V.T.) and by Biomedical Research grant by American Lung Society (RG-310669 to A.V.T.). References [1] N.H. Ruddle, Lymphotoxin and TNF: how it all began-a tribute to the travelers, Cytokine Growth Factor Rev. 25 (2) (2014) 83–89. [2] L.K. Ward-Kavanagh, W.W. Lin, J.R. Sedy, C.F. Ware, The TNF receptor superfamily in co-stimulating and co-inhibitory responses, Immunity 44 (5) (2016) 1005–1019. [3] C.F. Ware, Network communications: lymphotoxins, LIGHT, and TNF, Annu. Rev. Immunol. 23 (2005) 787–819. [4] C. Remouchamps, L. Boutaffala, C. Ganeff, E. Dejardin, Biology and signal transduction pathways of the Lymphotoxin-alphabeta/LTbetaR system, Cytokine Growth Factor Rev. 22 (5–6) (2011) 301–310. [5] A.V. Tumanov, E.P. Koroleva, X. Guo, Y. Wang, A. Kruglov, S. Nedospasov, Y.X. Fu, Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge, Cell Host Microbe 10 (1) (2011) 44–53. [6] Y. Wang, E.P. Koroleva, A.A. Kruglov, D.V. Kuprash, S.A. Nedospasov, Y.X. Fu, A. V. Tumanov, Lymphotoxin beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection, Immunity 32 (3) (2010) 403–413. [7] A.V. Tumanov, P.A. Christiansen, Y.-X. Fu, The role of lymphotoxin receptor signaling in diseases, Curr. Mol. Med. 7 (6) (2007) 567–578. [8] Y.X. Fu, D.D. Chaplin, Development and maturation of secondary lymphoid tissues, Annu. Rev. Immunol. 17 (1999) 399–433. [9] T.D. Randall, D.M. Carragher, J. Rangel-Moreno, Development of secondary lymphoid organs, Annu. Rev. Immunol. 26 (2008) 627–650. [10] T.W. Spahn, H.P. Eugster, A. Fontana, W. Domschke, T. Kucharzik, Role of lymphotoxin in experimental models of infectious diseases: potential

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