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• W2022004231 abstract "•A novel TRAIL+ NK cell subset regulates immune responses in chronic viral infection•TRAIL+ NK cells eliminate activated CD4+ T cells, but lack antiviral capacity•Development of autoimmune disease is constrained by TRAIL+ NK cells Natural killer (NK) cells have been reported to control adaptive immune responses that occur in lymphoid organs at the early stages of immune challenge. The physiological purpose of such regulatory activity remains unclear, because it generally does not confer a survival advantage. We found that NK cells specifically eliminated activated CD4+ T cells in the salivary gland during chronic murine cytomegalovirus (MCMV) infection. This was dependent on TNF-related apoptosis inducing ligand (TRAIL) expression by NK cells. Although NK cell-mediated deletion of CD4+ T cells prolonged the chronicity of infection, it also constrained viral-induced autoimmunity. In the absence of this activity, chronic infection was associated with a Sjogren’s-like syndrome characterized by focal lymphocytic infiltration into the glands, production of autoantibodies, and reduced saliva and tear secretion. Thus, NK cells are an important homeostatic control that balances the efficacy of adaptive immune responses with the risk of developing autoimmunity. Natural killer (NK) cells have been reported to control adaptive immune responses that occur in lymphoid organs at the early stages of immune challenge. The physiological purpose of such regulatory activity remains unclear, because it generally does not confer a survival advantage. We found that NK cells specifically eliminated activated CD4+ T cells in the salivary gland during chronic murine cytomegalovirus (MCMV) infection. This was dependent on TNF-related apoptosis inducing ligand (TRAIL) expression by NK cells. Although NK cell-mediated deletion of CD4+ T cells prolonged the chronicity of infection, it also constrained viral-induced autoimmunity. In the absence of this activity, chronic infection was associated with a Sjogren’s-like syndrome characterized by focal lymphocytic infiltration into the glands, production of autoantibodies, and reduced saliva and tear secretion. Thus, NK cells are an important homeostatic control that balances the efficacy of adaptive immune responses with the risk of developing autoimmunity. Natural killer (NK) cells, a prototypical component of innate immunity, are rapidly recruited to sites of cellular transformation or intracellular infection (Vivier et al., 2008Vivier E. Tomasello E. Baratin M. Walzer T. Ugolini S. Functions of natural killer cells.Nat. Immunol. 2008; 9: 503-510Crossref PubMed Scopus (2510) Google Scholar) and, depending on a delicate balance of signals mediated by activating and inhibitory receptors, promptly mediate cytotoxic activities or cytokine secretion (Lanier, 2008Lanier L.L. Up on the tightrope: natural killer cell activation and inhibition.Nat. Immunol. 2008; 9: 495-502Crossref PubMed Scopus (1185) Google Scholar). Additional functions of NK cells have been uncovered in recent years that demonstrate their role in immunoregulation (Biron, 2012Biron C.A. Yet another role for natural killer cells: cytotoxicity in immune regulation and viral persistence.Proc. Natl. Acad. Sci. USA. 2012; 109: 1814-1815Crossref PubMed Scopus (21) Google Scholar, Degli-Esposti and Smyth, 2005Degli-Esposti M.A. Smyth M.J. Close encounters of different kinds: dendritic cells and NK cells take centre stage.Nat. Rev. Immunol. 2005; 5: 112-124Crossref PubMed Scopus (472) Google Scholar). Evidence points to immunoregulatory functions being elicited in the early stages of the immune response (Andrews et al., 2010Andrews D.M. Estcourt M.J. Andoniou C.E. Wikstrom M.E. Khong A. Voigt V. Fleming P. Tabarias H. Hill G.R. van der Most R.G. et al.Innate immunity defines the capacity of antiviral T cells to limit persistent infection.J. Exp. Med. 2010; 207: 1333-1343Crossref PubMed Scopus (170) Google Scholar, Lang et al., 2012Lang P.A. Lang K.S. Xu H.C. Grusdat M. Parish I.A. Recher M. Elford A.R. Dhanji S. Shaabani N. Tran C.W. et al.Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity.Proc. Natl. Acad. Sci. USA. 2012; 109: 1210-1215Crossref PubMed Scopus (241) Google Scholar, Lee et al., 2009Lee S.H. Kim K.S. Fodil-Cornu N. Vidal S.M. Biron C.A. Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection.J. Exp. Med. 2009; 206: 2235-2251Crossref PubMed Scopus (165) Google Scholar, van Dommelen et al., 2006van Dommelen S.L. Sumaria N. Schreiber R.D. Scalzo A.A. Smyth M.J. Degli-Esposti M.A. Perforin and granzymes have distinct roles in defensive immunity and immunopathology.Immunity. 2006; 25: 835-848Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, Waggoner et al., 2012Waggoner S.N. Cornberg M. Selin L.K. Welsh R.M. Natural killer cells act as rheostats modulating antiviral T cells.Nature. 2012; 481: 394-398Google Scholar), but very little is known about the potential activities of NK cells at later times, especially in chronic inflammatory pathologies associated with persistent viral infections. Furthermore, the role of NK cells in tissue-specific immune responses is unknown. There has been a growing appreciation of the influence of NK cells on the adaptive immune response. NK cell depletion prior to infection enhances the CD8+ T cell response against lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV) (Andrews et al., 2010Andrews D.M. Estcourt M.J. Andoniou C.E. Wikstrom M.E. Khong A. Voigt V. Fleming P. Tabarias H. Hill G.R. van der Most R.G. et al.Innate immunity defines the capacity of antiviral T cells to limit persistent infection.J. Exp. Med. 2010; 207: 1333-1343Crossref PubMed Scopus (170) Google Scholar, Su et al., 2001Su H.C. Nguyen K.B. Salazar-Mather T.P. Ruzek M.C. Dalod M.Y. Biron C.A. NK cell functions restrain T cell responses during viral infections.Eur. J. Immunol. 2001; 31: 3048-3055Crossref PubMed Scopus (126) Google Scholar). In the case of LCMV, the elimination of CD8+ T cells by NK cells involves 2B4, natural killer group 2, member D (NKG2D) and perforin-mediated activities (Lang et al., 2012Lang P.A. Lang K.S. Xu H.C. Grusdat M. Parish I.A. Recher M. Elford A.R. Dhanji S. Shaabani N. Tran C.W. et al.Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity.Proc. Natl. Acad. Sci. USA. 2012; 109: 1210-1215Crossref PubMed Scopus (241) Google Scholar, Waggoner et al., 2010Waggoner S.N. Taniguchi R.T. Mathew P.A. Kumar V. Welsh R.M. Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis.J. Clin. Invest. 2010; 120: 1925-1938Crossref PubMed Scopus (104) Google Scholar). In addition, activated NK cells can eliminate activated CD4+ T cells in a perforin-mediated manner and thereby affect the CD8+ T cell functions required for effective viral clearance (Waggoner et al., 2012Waggoner S.N. Cornberg M. Selin L.K. Welsh R.M. Natural killer cells act as rheostats modulating antiviral T cells.Nature. 2012; 481: 394-398Google Scholar). In contrast, there is no evidence for the direct regulation of the CD8+ T cell response by NK cells during MCMV infection. Instead, the elimination of infected dendritic cells by NK cells limits the activation of T cells (Andrews et al., 2010Andrews D.M. Estcourt M.J. Andoniou C.E. Wikstrom M.E. Khong A. Voigt V. Fleming P. Tabarias H. Hill G.R. van der Most R.G. et al.Innate immunity defines the capacity of antiviral T cells to limit persistent infection.J. Exp. Med. 2010; 207: 1333-1343Crossref PubMed Scopus (170) Google Scholar). In other settings, such as transplantation or the development of autoimmunity, NK cells also limit T cell activation, though the mechanisms have yet to be clearly defined (Crome et al., 2013Crome S.Q. Lang P.A. Lang K.S. Ohashi P.S. Natural killer cells regulate diverse T cell responses.Trends Immunol. 2013; 34: 342-349Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). The role of NK cells in chronic inflammatory situations, especially in nonlymphoid tissues, is poorly defined and indeed most published studies have focused on tissue-specific T cell responses (Burzyn et al., 2013Burzyn D. Benoist C. Mathis D. Regulatory T cells in nonlymphoid tissues.Nat. Immunol. 2013; 14: 1007-1013Crossref PubMed Scopus (269) Google Scholar, Heath and Carbone, 2013Heath W.R. Carbone F.R. The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells.Nat. Immunol. 2013; 14: 978-985Crossref PubMed Scopus (249) Google Scholar, Mueller et al., 2013Mueller S.N. Gebhardt T. Carbone F.R. Heath W.R. Memory T cell subsets, migration patterns, and tissue residence.Annu. Rev. Immunol. 2013; 31: 137-161Crossref PubMed Scopus (532) Google Scholar). As far as NK cells are concerned, the focus has been on responses elicited in lymphoid organs in the early stages of immune challenge (Andrews et al., 2010Andrews D.M. Estcourt M.J. Andoniou C.E. Wikstrom M.E. Khong A. Voigt V. Fleming P. Tabarias H. Hill G.R. van der Most R.G. et al.Innate immunity defines the capacity of antiviral T cells to limit persistent infection.J. Exp. Med. 2010; 207: 1333-1343Crossref PubMed Scopus (170) Google Scholar, Lee et al., 2009Lee S.H. Kim K.S. Fodil-Cornu N. Vidal S.M. Biron C.A. Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection.J. Exp. Med. 2009; 206: 2235-2251Crossref PubMed Scopus (165) Google Scholar, Su et al., 2001Su H.C. Nguyen K.B. Salazar-Mather T.P. Ruzek M.C. Dalod M.Y. Biron C.A. NK cell functions restrain T cell responses during viral infections.Eur. J. Immunol. 2001; 31: 3048-3055Crossref PubMed Scopus (126) Google Scholar, van Dommelen et al., 2006van Dommelen S.L. Sumaria N. Schreiber R.D. Scalzo A.A. Smyth M.J. Degli-Esposti M.A. Perforin and granzymes have distinct roles in defensive immunity and immunopathology.Immunity. 2006; 25: 835-848Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, Waggoner et al., 2012Waggoner S.N. Cornberg M. Selin L.K. Welsh R.M. Natural killer cells act as rheostats modulating antiviral T cells.Nature. 2012; 481: 394-398Google Scholar). Furthermore, in the settings examined to date, NK cells contribute to viral persistence or pathology, which seems contradictory and leaves the physiological purpose of these activities unclear. Here, we define a novel interaction between NK cells and CD4+ T cells during chronic viral infection in vivo. This interaction occurs in a nonlymphoid tissue, specifically involves TRAIL-expressing NK cells, and results in the elimination of activated CD4+ T cells. Notably, we show that via these interactions, NK cells balance the efficacy of adaptive immune responses with the development of autoimmunity. Chronic MCMV infection in the salivary glands (SGs) of BALB/c mice is controlled by CD4+ T cells, independently of CD8+ T cells (Andrews et al., 2010Andrews D.M. Estcourt M.J. Andoniou C.E. Wikstrom M.E. Khong A. Voigt V. Fleming P. Tabarias H. Hill G.R. van der Most R.G. et al.Innate immunity defines the capacity of antiviral T cells to limit persistent infection.J. Exp. Med. 2010; 207: 1333-1343Crossref PubMed Scopus (170) Google Scholar). Interestingly, we found that the number of NK cells in the SGs of BALB/c mice increased significantly after MCMV infection (Figure 1A). The SG-resident NK cells in naive BALB/c mice showed a phenotype similar to that reported previously for C57BL/6 mice (Figure 1B, filled histogram; Tessmer et al., 2011Tessmer M.S. Reilly E.C. Brossay L. Salivary gland NK cells are phenotypically and functionally unique.PLoS Pathog. 2011; 7: e1001254Crossref PubMed Scopus (51) Google Scholar). After MCMV infection, NK cells localized to the SGs expressed increased amounts of cell surface markers associated with maturation and/or activation (Figure 1B, bold line). Of particular interest was the finding that, in the SGs, NK cells expressing TRAIL increased after MCMV infection (Figures 1C and 1D); this was not observed in other tissues (Figure S1 available online). A subset of NK cells that reside in the liver express TRAIL, as described previously (Takeda et al., 2005Takeda K. Cretney E. Hayakawa Y. Ota T. Akiba H. Ogasawara K. Yagita H. Kinoshita K. Okumura K. Smyth M.J. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver.Blood. 2005; 105: 2082-2089Crossref PubMed Scopus (216) Google Scholar); however, despite an increase in total NK cell numbers during acute infection (Figure 1E), the absolute number of hepatic TRAIL+ NK cells remained unaffected (Figure 1F). Indeed, at the peak of NK cell expansion (day 10 pi), the frequency of TRAIL+ NK cells in the liver declined (Figure S1B). In the SGs, TRAIL was exclusively expressed on NK cells and not on other lymphocyte populations localizing to this tissue after MCMV infection (Figures S1C–S1G). Altogether these data demonstrate that a population of NK cells expressing TRAIL accumulates specifically in the SGs during chronic MCMV infection. TRAIL has the capacity to induce apoptosis of some types of cells (Falschlehner et al., 2009Falschlehner C. Schaefer U. Walczak H. Following TRAIL’s path in the immune system.Immunology. 2009; 127: 145-154Crossref PubMed Scopus (229) Google Scholar). The specific accumulation of TRAIL+ NK cells in the SGs may therefore be a mechanism to eliminate infected cells, and thus control MCMV infection at this site. We tested this possibility by infecting BALB/c mice that were TRAIL deficient (Trail–/–). Although MCMV replication in the SGs of Trail–/– mice was initially similar to that of wild-type (WT) mice, by day 25 pi MCMV titers in TRAIL-deficient mice were significantly lower than those in WT mice and continued to decrease faster, so that by day 32 they were close to the limit of detection in Trail–/– mice (Figure 2A). By day 40 pi, virus was not detectable in either WT or Trail–/– mice (data not shown). Analysis of viral loads in the peripheral organs of Trail–/– mice indicated that, in the absence of TRAIL, virus control was not hindered; indeed, it was slightly enhanced at later time points (Figure S2). TRAIL mediates its effects via engagement of the death receptor 5 (DR5) in mice (Wu et al., 1999Wu G.S. Burns T.F. Zhan Y. Alnemri E.S. El-Deiry W.S. Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor.Cancer Res. 1999; 59: 2770-2775PubMed Google Scholar). When BALB.Dr5–/– mice were infected with MCMV, control of the virus in the SGs was improved to a similar extent to that which occurred in Trail–/– mice (Figure 2B). These findings indicate that the accumulation of TRAIL+ NK cells in the SGs does not contribute to the control of MCMV, but rather delays the clearance of this virus. CD4+ T cells mediate control of MCMV in the SGs (Andrews et al., 2010Andrews D.M. Estcourt M.J. Andoniou C.E. Wikstrom M.E. Khong A. Voigt V. Fleming P. Tabarias H. Hill G.R. van der Most R.G. et al.Innate immunity defines the capacity of antiviral T cells to limit persistent infection.J. Exp. Med. 2010; 207: 1333-1343Crossref PubMed Scopus (170) Google Scholar). Examination of SG tissue sections from MCMV-infected mice demonstrated that NK cells were in close proximity to CD4+ T cells after MCMV infection (Figure 3A), with 30.56% ± 3.47% of NK cells making contact with CD4+ T cells. Furthermore, a large proportion of the CD4+ T cells infiltrating the SGs expressed DR5, the receptor for TRAIL (Figure 3B). These findings raised the possibility that NK cells might interact with CD4+ T cells within the SGs and thus influence the adaptive immune response to MCMV infection. To explore this possibility, we compared the CD4+ T cell response in WT mice with that in TRAIL-deficient mice. The number of CD4+ T cells in the SGs of MCMV-infected Trail–/– mice was similar to that of WT mice at day 10 pi, but by day 18 pi significantly larger numbers of CD4+ T cells were present in the SGs of Trail–/– mice (Figure 3C), as was the number of CD4+DR5+ T cells (Figure 3D). DR5 was expressed by activated CD4+ T cells, defined as displaying high amounts of CD44 (Figure 3E), and correlated with degranulation, measured by CD107a staining (Figure 3F). The numbers of CD4+ T cells coexpressing CD44hi and DR5 (Figure 3G) or CD107a and DR5 were both elevated in the absence of TRAIL (Figure 3H). Therefore, TRAIL expression directly influenced the number of activated CD4+ T cells present in the SGs. Both CD4+ (Figure 3B) and CD8+ (data not shown) T cells express the TRAIL receptor during MCMV infection. However, the frequency of DR5+CD8+ T cells is 5-fold lower than that of DR5+CD4+ T cells in the SGs (7.68% ± 0.87% versus 27.53% ± 1.39% at day 18 pi). The CD8+ T cell population is not affected by the presence of TRAIL+ NK cells, suggesting that additional interactions are required for the elimination of DR5+CD4+ T cells. NKG2D is an activating NK cell receptor whose ligands are expressed on infected or stressed cells (Raulet et al., 2013Raulet D.H. Gasser S. Gowen B.G. Deng W. Jung H. Regulation of ligands for the NKG2D activating receptor.Annu. Rev. Immunol. 2013; 31: 413-441Crossref PubMed Scopus (564) Google Scholar). NKG2D expression was increased on ∼40% of SG NK cells during the course of MCMV infection (Figure 4A) and at higher amounts on TRAIL+ NK cells (Figure 4B). In addition to stressed and infected cells, NKG2D ligands can be expressed on activated T cells (Cerboni et al., 2007Cerboni C. Zingoni A. Cippitelli M. Piccoli M. Frati L. Santoni A. Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis.Blood. 2007; 110: 606-615Crossref PubMed Scopus (231) Google Scholar, Rabinovich et al., 2003Rabinovich B.A. Li J. Shannon J. Hurren R. Chalupny J. Cosman D. Miller R.G. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells.J. Immunol. 2003; 170: 3572-3576Crossref PubMed Scopus (183) Google Scholar). When the expression of NKG2D ligands was evaluated on T cells from the SGs of MCMV-infected mice, it was found to be largely restricted to the CD4+ T cell population (Figure 4C). More than 40% of CD4+ T cells expressed NKG2D ligands at day 18 pi, compared to less than 10% of CD8+ T cells (Figure 4D). Expression of NKG2D ligands on CD4+ T cells was restricted to the CD44hi subset; more than half of these cells also coexpressed the TRAIL receptor DR5 (Figure 4E). These data show that during MCMV infection, NKG2D ligands are preferentially expressed on CD4+ T cells and probably contribute to interactions with NKG2D+TRAIL+ NK cells in the SGs. Depletion experiments were performed in Trail–/– mice to determine whether CD4+ T cells were required for viral control in the absence of TRAIL. TRAIL-deficient mice were specifically depleted of CD4+ or CD8+ T cells from day 9 pi and viral titers in the SGs measured at day 25 pi. Although depletion of CD8+ T cells had no impact on the viral load within the SGs, the viral load within the SGs of Trail–/– mice depleted of CD4+ T cells was significantly higher (Figure 5A). Taken together, these data suggest that TRAIL expression by NK cells accumulating in the SGs acts to eliminate CD4+ T cells and consequently delays viral clearance. To demonstrate that NK cells restrain the CD4+ T cell response, we depleted NK cells after infection. For these experiments we made use of the BALB.B6-CT6 (CT6) congenic mouse strain (Scalzo et al., 1999Scalzo A.A. Brown M.G. Chu D.T. Heusel J.W. Yokoyama W.M. Forbes C.A. Development of intra-natural killer complex (NKC) recombinant and congenic mouse strains for mapping and functional analysis of NK cell regulatory loci.Immunogenetics. 1999; 49: 238-241Crossref PubMed Scopus (47) Google Scholar). This mouse strain has the advantage that it expresses the NK1.1 receptor (absent in BALB/c mice), but like the BALB/c strain lacks the Ly49H activating NK cell receptor. CT6 mice were infected with MCMV, and NK cells were specifically depleted using the anti-NK1.1 antibody PK136 from day 9 pi. Mice depleted of NK cells had a significantly lower viral burden in the SGs at day 25 pi compared to nondepleted mice (Figure 5B). Furthermore, the percentage and total number of DR5+CD4+ T cells localized to the SGs was significantly increased in the absence of NK cells (Figures 5C and 5D). In an additional strategy, we adoptively transferred WT naive NK cells into TRAIL-deficient mice at day 4 pi and assessed viral loads in the SGs at day 25 pi. The transfer of WT NK cells into TRAIL-deficient mice resulted in a significant increase in the viral burden within the SGs (Figure 5E). Viral loads in the SGs were not altered when TRAIL-deficient NK cells were transferred into TRAIL-deficient mice or when WT NK cells were transferred into WT hosts (Figure 5E). Notably, transferring WT TRAIL-sufficient NK cells into Trail–/– hosts resulted in a significant decrease in the number of DR5+CD4+ T cells (Figure 5F), clearly demonstrating a causative impact of NK cell TRAIL on this phenotype. Together these data establish that NK cells limit the antiviral CD4+ T cell response within the SGs through a TRAIL-dependent mechanism. Several systemic autoimmune diseases have been postulated to associate with viral infections (Getts et al., 2013Getts D.R. Chastain E.M. Terry R.L. Miller S.D. Virus infection, antiviral immunity, and autoimmunity.Immunol. Rev. 2013; 255: 197-209Crossref PubMed Scopus (153) Google Scholar). We hypothesized that by restraining the CD4+ T cell response during MCMV infection, NK cells may reduce the chance of autoimmunity developing. We therefore analyzed the generation of autoantibodies in WT and TRAIL-deficient mice and found that after MCMV infection TRAIL-deficient mice had higher serum concentrations of antibodies reactive against proteins present in SG homogenates (Figure 6A), suggesting that they may be developing an autoimmune disease affecting this organ. Sjogren’s syndrome (SS) is the second most common systemic autoimmune disease. The disease affects salivary and lacrimal glands and leads to exocrine dysfunction characterized by the loss of saliva and tear production (Mavragani and Moutsopoulos, 2010Mavragani C.P. Moutsopoulos H.M. The geoepidemiology of Sjögren’s syndrome.Autoimmun. Rev. 2010; 9: A305-A310Crossref PubMed Scopus (218) Google Scholar). SS is characterized by focal lymphocytic infiltration into the glands and the formation of aggregates resembling ectopic germinal center-like structures in exocrine tissues (Bombardieri and Pitzalis, 2012Bombardieri M. Pitzalis C. Ectopic lymphoid neogenesis and lymphoid chemokines in Sjogren’s syndrome: at the interplay between chronic inflammation, autoimmunity and lymphomagenesis.Curr. Pharm. Biotechnol. 2012; 13: 1989-1996Crossref PubMed Scopus (41) Google Scholar). Histological examination of SGs from WT and TRAIL-deficient mice revealed the presence of lymphocytic aggregates from day 40 postinfection. These structures were very different from the disseminated lymphocytic infiltration observed during the viremic phase of SG infection (up to day 32) (data not shown) and were found up to 120 days postinfection and localized around acini and ducts (Figure 6B). These data demonstrate that MCMV infection leads to an inflammatory response in SGs of TRAIL-deficient mice that has the histopathological hallmarks of SS. A key feature of SS is the production of autoantibodies, in particular anti-Ro/SSA and anti-La/SSB (Kyriakidis et al., 2014Kyriakidis N.C. Kapsogeorgou E.K. Tzioufas A.G. A comprehensive review of autoantibodies in primary Sjögren’s syndrome: clinical phenotypes and regulatory mechanisms.J. Autoimmun. 2014; 51: 67-74Crossref PubMed Scopus (98) Google Scholar). Production of these autoantibodies was assessed using a specific mouse ELISA. Anti-Ro antibodies were detected in the sera of MCMV-infected mice from day 40 postinfection, and titers were significantly higher in sera collected from infected TRAIL-deficient mice compared to infected WT mice at all the time points tested (Figure 6C). These data demonstrate that the production of autoantibodies associated with SS is promoted by viral infection and is limited by a TRAIL-dependent mechanism. Ultimately, the principal defect in SS is the inability to produce saliva and tears. Saliva secretion was measured after pilocarpine stimulation in age-matched WT and TRAIL-deficient mice infected with MCMV. At day 80 postinfection, there was a significant difference in saliva flow between WT and TRAIL-deficient mice, the latter showing reduced saliva production (Figure 6D). To confirm that TRAIL+ NK cells mediated the phenotype, we depleted NK cells from MCMV-infected mice from day 9 after infection and then measured saliva production as above. As noted in the absence of TRAIL, in the absence of NK cells, MCMV-infected WT mice showed decreased saliva production compared to WT mice with an intact NK cell response (Figure 6E). In addition to the SGs, SS affects the functionality of lacrimal glands, and exocrine dysfunction in this tissue results in loss of tear production. In MCMV-infected WT mice depleted of NK cells, tear production was significantly reduced compared to undepleted WT controls (Figure 6F). Altogether these data demonstrate that after MCMV infection, mice lacking TRAIL on NK cells develop an autoimmune disease with histopathological, clinical, and physiological features of SS. Our data provide clear evidence for the influence of NK cells on the adaptive immune response to chronic viral infection in a nonlymphoid tissue. NK cells specifically accumulate in the SGs as part of the local inflammatory response to infection, and a significant proportion express TRAIL. TRAIL was originally identified on the basis of its homology with TNF and its capacity to induce apoptosis in tumor cells (Wiley et al., 1995Wiley S.R. Schooley K. Smolak P.J. Din W.S. Huang C.P. Nicholl J.K. Sutherland G.R. Smith T.D. Rauch C. Smith C.A. et al.Identification and characterization of a new member of the TNF family that induces apoptosis.Immunity. 1995; 3: 673-682Abstract Full Text PDF PubMed Scopus (2656) Google Scholar). TRAIL mediates its apoptotic effects via specific death receptors that are typically absent from normal cells and tissues. Thus, TRAIL-deficient mice exhibit increased susceptibility to both tumor initiation and metastasis (Almasan and Ashkenazi, 2003Almasan A. Ashkenazi A. Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy.Cytokine Growth Factor Rev. 2003; 14: 337-348Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, Takeda et al., 2001Takeda K. Hayakawa Y. Smyth M.J. Kayagaki N. Yamaguchi N. Kakuta S. Iwakura Y. Yagita H. Okumura K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells.Nat. Med. 2001; 7: 94-100Crossref PubMed Scopus (595) Google Scholar), leading to the widely held view that the primary function of TRAIL is specific elimination of transformed cells during innate immune surveillance. However, TRAIL regulates the survival of a variety of other cell types, including cells of the immune system that upregulate TRAIL receptors when activated (Falschlehner et al., 2009Falschlehner C. Schaefer U. Walczak H. Following TRAIL’s path in the immune system.Immunology. 2009; 127: 145-154Crossref PubMed Scopus (229) Google Scholar). A partial role for NK cell TRAIL in eliminating hepatitis B virus-specific CD8+ T cells has been reported, but the study was not developed beyond an in vitro system (Peppa et al., 2013Peppa D. Gill U.S. Reynolds G. Easom N.J. Pallett L.J. Schurich A. Micco L. Nebbia G. Singh H.D. Adams D.H. et al.Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion.J. Exp. Med. 2013; 210: 99-114Crossref PubMed Scopus (247) Google Scholar). By contrast, our work clearly demonstrates NK cell-dependent, TRAIL-mediated killing of a physiologically important CD4+ T cell population in vivo, which results in limiting antiviral responses to curb the development of autoimmunity. The elimination of activated CD4+ T cells from the SGs by NK cells in a TRAIL-dependent manner resembles the elimination of activated neutrophils by NK cells, where TRAIL expression is crucial for the resolution of local inflammation (McGrath et al., 2011McGrath E.E. Marriott H.M. Lawrie A. Francis S.E. Sabroe I. Renshaw S.A. Dockrell D.H. Whyte M.K. TNF-related apoptosis-inducing ligand (TRAIL) regulates inflammatory neutrophil apoptosis and enhances resolution of inflammation.J. Leukoc. Biol. 2011; 90: 855-865Crossref PubMed Scopus (106) Google Scholar). Thus, the expression of TRAIL by NK cells may serve as a general mechanism by which NK cells limit the persistence of activated cells at sites of inflammation and infection, to encourage the resolution of the response. Notably, administration of recombinant TRAIL in a model of bacterial meningitis decreased inflammation, as well as apoptosis, suggesting that TRAIL may act as a potential anti-inflammatory agent (Hoffmann et al., 2007Hoffmann O. Priller J. Prozorovski T. Schulze-Topphoff U. Baeva N. Lunemann J.D. Aktas O. Mahrhofer C. Stricker S. Zipp F. Weber J.R. TRAIL limits excessive host immune responses in bacterial meningitis.J. Clin. Invest. 2007; 117: 2004-2013Crossref PubMed Scopus (63) Google Scholar). Autoi" @default.
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• W2022004231 date "2014-10-01" @default.
• W2022004231 modified "2023-10-12" @default.
• W2022004231 title "TRAIL+ NK Cells Control CD4+ T Cell Responses during Chronic Viral Infection to Limit Autoimmunity" @default.
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