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Stimulating Lymphotoxin Receptor on the Dendritic Cells Is Critical for Their Homeostasis and Expansion¹

Department of Pathology, University of Chicago, Chicago IL 60637

	Abstract

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The increased number of dendritic cells (DCs) inside lymphoid tissue may contribute to the enhanced priming of lymphocytes. The homeostasis of splenic DCs has mostly been attributed to their migration to the spleen via the chemokine microenvironment induced by lymphotoxin receptor (LTR) signaling on splenic stromal cells. In this study we show that the lack of direct LTR signaling on DCs is associated with the reduction of the number of DCs in the spleen independently of chemokine gradients. LTR^–/– mice have reduced DCs and reduced BrdU incorporation on DCs, and fewer DCs from LTR^–/– mice are detected in the spleen. Furthermore, increased expression of LIGHT (homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for herpes virus entry mediator on T cells) on T cells, a member of the TNF family (TNFSF14) and a ligand for LTR, could dramatically increase the number of T cells and DCs, which leads to severe autoimmune diseases in a LTR-dependent fashion. In vitro, LIGHT could directly promote accumulation of bone marrow-derived DCs. Furthermore, intratumor expression of LIGHT can dramatically expand DCs in situ, and inoculation of DCs into tumor tissues enhanced tumor immunity. Therefore, LTR signaling on DCs is required for their homeostasis during physiology and pathological conditions, and increased LIGHT-LTR interaction could stimulate DC expansion for T cell-mediated immunity.

	Introduction

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Dendritic cells (DCs)⁴ are positioned in the peripheral tissues to capture Ags. Upon maturation and activation, DCs migrate to the T cell zones of lymphoid tissues, presumably through a chemokine gradient, where they initiate immune responses or induce tolerance (1, 2, 3). The presence of DCs inside lymphoid tissues has often been attributed to their ability to express chemokine receptors mediating their migration. The dominant receptor in the mobilization of DCs from the periphery to lymphoid tissues is thought to be chemokine receptor CCR7 (4, 5). The ligands of CCR7 include secondary lymphoid tissue chemokine (CCL21) and EBV-induced molecule-1 ligand chemokine (CCL19), which are expressed by lymphatic endothelium and stromal cells as well as the endothelial cells in the lymph node. These chemokines were found to control the migration of DCs from peripheral tissues to lymph nodes (6, 7, 8).

Lymphotoxin (LT) and TNF pathways control CCL21 and CCL19 expression in the spleen, which may be critical for the migration and/or positioning of DCs in the spleen (6, 9). Consistently, LT or its receptor (LTR) knockout mice showed reduced numbers of DCs in the spleen (10). It was reasonable to propose that the LTR signaling-induced chemokine microenvironment mediated by the splenic stroma was critical for the recruitment of DCs into peripheral lymphoid tissues, but recent studies suggested the possibility of alternative pathways other than LT-mediated chemokine CCL19/CCL21 in the regulation of DCs’ homeostasis in lymphoid tissues. Murine CCL21, expressed in both lymphoid and nonlymphoid tissues, is encoded by two genes that are distinguished by a single nucleotide difference resulting in a leucine or serine discrepancy at position 65; one is expressed in lymphoid tissues and the other in peripheral tissues, including lymphatic vessels (11, 12). We have recently observed that LT regulates CCL21 in lymphoid tissues, but not in nonlymphoid tissues (13). Interestingly, plt mice, which lack both CCL21 and CCL19 in the lymphoid tissues, have comparable numbers of DCs to those in wild-type (wt) mice in the spleen. Although DCs were largely present in the T cell zone in wt mice, most DCs were outside the white pulp in plt mice (14). In addition, the lack of TNF, which also reduces the expression of these leukocyte-regulating chemokines, did not cause a decrease in the number of DCs in lymphoid tissues (10, 15). These lines of evidence raised the possibility that the number of DCs in the spleen may depend more on survival and proliferation signals delivered by LTR on DCs, whereas the chemokines only affect the localization of DCs inside the spleen. A very recent study has elegantly shown that intrinsic LTR is required for the homeostasis of lymphoid tissue DCs, and B cells expressing LT play a critical role in the increased proliferation of DC in the spleen of wt mice (16). Together, these studies suggest that DC proliferation is an important pathway for locally maintaining these cells in the steady state.

LIGHT (homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for herpes virus entry mediator (HVEM) on T cells, a receptor expressed by T lymphocytes; TNFSF14) is a TNF family member that also binds to LTR and two other distinct members of the TNFR family, the HVEM, and the soluble decoy receptor 3 (17, 18, 19, 20). LIGHT has a potent T cell costimulatory function affecting CTL-mediated tumor rejection, allograft rejection, and graft-vs-host disease (21). Constitutive expression of LIGHT on T cells in LIGHT-transgenic mice showed a massive accumulation of activated T cells, severe lymphoid proliferative disorder, and autoimmune disease as well as severe inflammation in the gut (22, 23). Consistently, LIGHT maps to the region overlapping a susceptibility locus for inflammatory bowel disease (IBD) on human chromosome 19p13.3 (24). Blocking LT/LIGHT binding by LTR-Ig in animal models can ameliorate the severity of various autoimmune diseases (20). These studies suggest that LIGHT is critical for the development of autoimmune diseases. The mechanism of LIGHT-mediated autoimmunity, however, has focused primarily on the costimulatory property of LIGHT on T cells. LIGHT seems to cooperate with CD40L to induce the maturation of monocyte-derived DCs (25) and is required for DC-mediated allogeneic T cell responses in vitro (26). In the current study we have observed that recombinant LIGHT can directly influence bone marrow (BM)-derived DC (BMDC) precursor cell proliferation in vitro, and LTR signaling is required for LIGHT-induced DC expansion. The lack of LTR on DCs results in impaired homeostasis. Furthermore, we have shown that LIGHT-transgenic (LIGHT-Tg) mice have increased numbers of DCs in an LTR-dependent fashion. Intratumoral expression of LIGHT can increase the number of DCs inside the tumor, leading to tumor rejection. Therefore, the DC turnover rate may be dependent on LTR signaling on DCs, and activation by the ligands for LTR may be a new way to stimulate and expand DC.

	Materials and Methods

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Mice

LIGHT-Tg mice were generated as previously described (23). The LIGHT cDNA was inserted into the AscI site of plck.E2 vector (gift from T. Hettmann, University of Chicago, Chicago, IL), which contains the proximal lck promoter, human growth hormone gene polyadenylation site, and locus control region elements from the human CD2 gene. LTR^–/– and HVEM^–/– mice were provided by Dr. K. Pfeffer (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Gemany). The plt mice were provided by Dr. J. G. Cyster (University of California, San Francisco, CA) (14, 27). C57BL/6 (B6) LIGHT-Tg mice were crossed to LTR^–/– mice in the B6 background. LIGHT-Tg mice were crossed to HVEM^–/– mice (crossed to B6 background for six generations) to obtain LIGHT-Tg/HVEM^–/– mice. Female C3B6F₁ mice, 4–8 wk of age, were purchased from the Frederick Cancer Research Facility of the National Cancer Institute. Animal experimentation protocols were consistent with National Institutes of Health guideline and were approved by the institutional animal care and use committee of University of Chicago.

Cell preparation and flow cytometry

Splenic DC were treated and collected according to a previously described method (10). In brief, spleen fragments were digested with 2 mg/ml collagenase and 100 µg/ml DNase for 30 min at 37°C and then gently pipetted in the presence of 0.01 M EDTA for 1 min. Single-cell suspensions were stained and analyzed by flow cytometry on a FACScan or FACSCalibur (BD Biosciences). Biotinylated anti-CD11c and CD11b (Mac-1), FITC-conjugated anti-I-A^b, anti-CD11c, and anti-CD8 Ab were all obtained from BD Pharmingen. LIGHT-expressing Ag104 or LIGHT-expressing Ag104Ld tumor were prepared as previously described (28).

Fusion proteins and in vitro proliferation assays

Generation of recombinant LIGHT was described previously (28). Stable-transfected FLAG-LIGHT Chinese hamster ovary cell supernatants were collected, and FLAG-LIGHT protein was purified using anti-FLAG M2-agarose affinity gel. For GM-CSF-induced splenocyte proliferation, the splenocytes (2 x 10⁵/well) from wt littermates or Tg mice were cultured in medium supplemented with GM-CSF (1 ng/ml; R&D Systems) for 48 h, pulsed with 1 µCi of [³H]thymidine for 16 h, and then harvested for liquid scintillation counting. BM-derived myeloid cells were obtained by culturing BM cells with GM-CSF according to the procedure developed by Lutz et al. (29). For LIGHT stimulation, recombinant LIGHT protein was precoated in 96-well plates at 4°C overnight. Suspension BM cells that had been cultured in the presence of GM-CSF for 6 days were collected and incubated to LIGHT-coated plates at 1 x 10⁵ cells/well for 48 h. The day before harvest, cells were pulsed with [³H]thymidine overnight.

BMDC

BM cells from femurs of wt or LTR^–/– mice were cultured in RPMI 1640 (Invitrogen Life Technologies) supplemented with 10% FCS (HyClone) and recombinant mouse GM-CSF (R&D Systems) according to procedure developed by Lutz et al. (29). For in vivo labeling with BrdU, 2 mg/mouse BrdU was injected i.p., and splenic DCs were isolated as described above. CD11c cells were gated, and incorporation of BrdU was determined using a BrdU flow kit (BD Pharmingen).

	Results

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Increased number of DC in LIGHT-Tg mice

Constitutive expression of LIGHT on T cells in LIGHT-Tg mice resulted in a systemic increase in T cell activation and expansion before the development of lymphoproliferative disorders (22, 23, 30). LTR signaling is required for the homeostasis of splenic DCs (10), which may be critical for the homeostasis and activation of T cells. It raises the possibility that increased LIGHT expression, a ligand for LTR, may enhance LTR signaling on DCs, which subsequently influences the homeostasis of DCs. To test whether LIGHT-mediated T cell expansion is associated with the expansion of DCs, we first determined the number of DCs from the spleens of wt and LIGHT-Tg mice. The total number and percentage of DCs (CD11c⁺ cells) were impressively increased in the spleens (as well as mesenteric lymph nodes) of Tg mice (Fig. 1, A and B, and data not shown for mesenteric lymph nodes) with a 10- to 15-fold increase in the total number of DCs in the spleens of Tg mice compared with that in wt mice. The percentage of CD11c^–/MHC class II⁺ cells (B cells) was strongly decreased in Tg mice (Fig. 1A), which might be the result of a stronger T cell expansion. Using BrdU labeling, more dividing DCs were found in the spleens of LIGHT-Tg mice, suggesting that an increase in proliferation may play a role in the increased DCs in these mice (Fig. 1C). The CD11c⁺ DC subsets that were mostly increased in LIGHT-Tg mice were CD8^–CD11b⁺ cells, a subset of DCs triggering immunity rather than tolerance (Fig. 1A). Therefore, increasedLIGHT expression on T cells may contribute to the increase in myeloid DCs.

View larger version (26K): [in this window] [in a new window]   FIGURE 1. Increase in DCs in the spleen of LIGHT Tg mice. A, The percentage of DCs is increased in the spleens of LIGHT-Tg mice. Spleens of 16- to 18-wk-old WT and LIGHT Tg mice were collected and stained with CD11c and I-Ab Ab and analyzed by FACS. The DC subsets were stained with CD11c/CD11b/CD8. One representative experiment of five is shown. B, The total number of DCs is increased in the spleen of LIGHT-Tg mice. Splenocytes were stained with CD11c Ab. The total number of CD11c+ cells was calculated after FACS analysis. C, The total number of BrdU+ DCs was increased in the spleens of LIGHT Tg mice. BrdU (2 mg/mouse) was injected i.p., splenic DC were isolated 24 h later, CD11c cells were gated, and incorporation of BrdU was determined using a BrdU flow kit (BD Pharmingen).

View larger version (68K): [in this window] [in a new window]   FIGURE 2. LTR, but not HVEM, signaling is required for the LIGHT-mediated DC increase. A, Reduced DCs in the absence of LTR signaling, but not of HVEM signaling. The percentages of DCs in WT, Tg, LTR–/–, and Tg/LTR–/– were determined by FACS. Three to five mice in each background were used. B, The percentages of DCs in WT, Tg, HVEM–/–, and Tg/HVEM–/– were analyzed as described in A. C, Distribution of DC clusters determined by immunohistology. The frozen spleen sections from the indicated mice were stained for CD11c (brown) and B220 (blue). The mouse data from one of three experiments are presented. Reduced number and size of the splenic DC can be visualized in the spleens of LTR–/– and Tg/LTR–/– mice.

To directly test the ability of LIGHT in stimulating precursors of myeloid DCs, BM cells were treated with GM-CSF for 6 days to induce differentiation and proliferation of DC lineage. LIGHT could directly induce accumulation of immature myeloid DC after an initial treatment of BM cells with GM-CSF for 6 days (Fig. 3A). This effect was dose dependent (Fig. 3B) and LIGHT specific, because it was blocked by LTR-Ig and HVEM-Ig (data not shown). The major cells recovered in the presence of either LIGHT or GM-CSF were CD11c⁺CD11b⁺ DC (data not shown). However, the stimulatory effect was not detected when fresh, undifferentiated BM cells were used (Fig. 3A). These results suggested that LIGHT could directly increase immature DC number. To determine whether LIGHT-induced LTR signaling could directly induce the proliferation of DC lineage, an anti-LTR agonist Ab (9B10.7) was used to treat BM cells that had been cultured with GM-CSF for 3 days, as shown in Fig. 3C. Anti-LTR Ab could stimulate the proliferation of DC precursor, which is consistent with the recent report by Kabashima et al. (16). Purified CD11c⁺ cells from such BM culture fail to proliferate after stimulation with 9B10.7. This indicated that LTR signaling could directly induce immature DC proliferation.

View larger version (25K): [in this window] [in a new window]   FIGURE 3. LIGHT can promote DC accumulation in vitro. A, LIGHT can only function after BM cell differentiation induced by GM-CSF. BM cells were freshly collected on day 0 or 6 after culture with 20 ng/ml GM-CSF. LIGHT or GM-CSF (as a positive control) was then added to the culture, and cell proliferation for another 2 days was monitored by [3H]TdR incorporation. B, LIGHT-induced BM cell proliferation is dose dependent. Different concentrations of LIGHT protein were coated in 96-well plates overnight, BM cells that had been treated with GM-CSF for 6 days were added at 1 x 105/well, and cell proliferation was monitored by [3H]TdR incorporation after 48-h incubation. C, LTR signaling can promote DC accumulation. BM cells were cultured in GM-CSF for 3 days, then labeled with CFSE, and cultured with or without 1.8 µg/ml anti-LTR agonist Ab (9B10.7) for another 3 days. The CFSElow population indicated cell proliferation.

LTR signaling on DC is required for homeostasis of DC

The DC turnover rate in the spleen is rather high, but which cytokine pathway is required for DC homeostasis is unclear. LTR pathway-deficient mice showed reduced numbers of DCs in the spleen, which was proposed to be due to reduced CCL21/CCL19 (6, 9, 10). A recent study by Cyster’ group (16) indicated that DC proliferation is an important pathway for locally maintaining these cells in the steady state, in an LTR-dependent fashion. We have found that there is more accumulation of DCs in BMDC culture with additional agonistic Ab treatment. To address LTR-mediated CCL21 or CCL19 is not essential for the presence of DCs in the spleen; plt mice, which lack both CCL21 and CCL19, had similar number of splenic DCs compared with wt mice (Fig. 4). The presence of DCs in plt mice was still dependent on LTR signaling, because the number of splenic DCs in plt mice was reduced 60–75% after treatment with soluble LTR-Ig for 14 days. The degree of reduction of DCs is very similar to that of wt mice treated with LTR-Ig or to that in LTR^–/– spleen without treatment (Fig. 4). The data suggest that LTR signaling is required for the homeostasis of splenic DCs relatively independently of CCL21/CCL19.

View larger version (73K): [in this window] [in a new window]   FIGURE 4. Signaling via LTR is required for the presence of DCs in the spleen without chemokine secondary lymphoid tissue chemokine, EBV-induced molecule-1 ligand chemokine expression. A single dose of LTR-Ig (100 µg) was administrated i.p. into plt mice, and the spleens were collected 2 wk later. The distribution of DC clusters was determined by immunohistology (A), and the number of DCs was determined by FACS analysis. One of three experiments is presented. Three mice in each group were used in each experiment.

View larger version (19K): [in this window] [in a new window]   FIGURE 5. An LTR signal on DC is required for DC homeostasis. Wt or LTR–/– mice were treated with BrdU overnight, splenic DCs were isolated, and CD11c cells were gated to determine their BrdU incorporation. Three mice in each group were used.

The low recovery of DC inside tumor may be due to the low amount of LIGHT produced by activated T cells there. It is possible that the expression of LIGHT inside tumor can increase the number of DCs, which could promote a stronger immune response against a very aggressive tumor, Ag104L^d, for which as little as 10⁴ cells can kill 100% of wt mice in 5–6 wk. LIGHT-expressing tumor cells (both Ag104 and Ag104L^d) were s.c. inoculated (28). We explored whether locally expressed LIGHT inside tumor can increase the number of DCs, which may play a critical role in T cell-mediated tumor rejection. The numbers of DCs inside the tumors in the presence or the absence of LIGHT were analyzed weekly. Impressively, LIGHT expression on the tumor tissue induced a dramatic increase in CD11b⁺CD11C⁺ DCs inside the tumor (Fig. 6, A and B). Compared with parental tumor, LIGHT-expressing tumor had higher BrdU incorporation on DCs, suggesting that DCs were actively proliferating. Furthermore, all LIGHT-transfected tumors were rejected (20 of 20 at either dose of 10⁵ or 10⁶ cells), whereas all parent tumors grew rapidly. Even inoculation of a much higher dose, a 1000-fold increase over the lethal dose, of LIGHT-expressing tumor cells (as high as 10⁷) led to rapid rejection of the tumor in 3–4 wk (20 of 20 mice). The increase in DCs may itself lead to strong antitumor responses, because BMDC intratumorally injected into well-established Ag104L^d tumor tissues lead to the delayed growth of tumor (Fig. 6C) or rapid rejection of these aggressive tumors (six of eight tumors in the treated group were rejected, whereas zero of eight tumors in the control group were rejected). This result indicated that intratumor expression of LIGHT leads to the dramatic increase in the number of intratumor DCs, which could contribute to a strong protective immune response.

View larger version (45K): [in this window] [in a new window]   FIGURE 6. LIGHT-expressing tumor increases the number of DCs, and increased DC number is associated with tumor rejection. Increased CD11c DCs were detected inside tumor (A and B). Ag104Ld or Ag104Ld-LIGHT tumor was inoculated into B6C3F1 mice, tumor was established for 2–3 wk, and tumor mass was removed and stained for CD11c/CD11b (A). Immunohistological analysis of DCs in the tumor showed increased DC number inside tumor tissues expressing LIGHT (B). Intratumor injection of DC retarded tumor growth (C). Intratumor injection of 1 x 106 BMDC into Ag104Ld tumor, which was inoculated 2 wk ago. Such treatment could lead to the rejection of most Ag104Ld tumor (six of eight), whereas all untreated mice showed progressive tumor without any rejection (zero of eight).

	Discussion

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The homeostasis of DCs in the spleen may depend more on proliferation signals delivered by LTR on DCs, whereas the fine localization of DCs may have a stronger dependence on local chemokine expression. The DC turnover rate is high in the spleen, and the molecular mechanisms that control their homeostasis have not been well defined. Our study has indicated that LTR signaling is essential for the homeostasis of splenic DCs. Because LT-deficient mice, but not LIGHT-deficient mice, show reduced splenic DC numbers, it is likely that during the physiological condition LT is more important for the number of DCs.

During inflammation and active T cell-mediated immune responses, LIGHT may be up-regulated on T cells. We have observed increased of LIGHT in the gut of IBD patients (data not shown). Increased expression of LIGHT on T cells causes massive T cell activation and expansion, leading to the development of lethal autoimmunity (22, 23). LIGHT-expressing tumor tissues induce substantial activation and expansion of T cells inside the tumor, leading to the eventual rejection (28). Complimentarily, blocking LTR-Ig signaling in animal models can ameliorate the severity of various autoimmune diseases (20). However, the mechanisms of LIGHT/LTR-mediated immunity are complicated and have been primarily attributed to its ability to costimulate T cells. In this study, we demonstrated that LIGHT, a ligand expressed on activated T cells, could directly expand DCs, which could further expand the T cell compartment to elicit autoimmunity or an antitumor response. Furthermore, our study also revealed that LTR signaling is required for the homeostasis of DCs in lymphoid tissues. Introducing LIGHT inside the tumor can dramatically influence the number of DCs in the tumor microenvironment, whereas the direct inoculation of DC into the tumor can result in the rejection of tumor. These data suggest the critical nature of LTR signaling on DCs for their presence in lymphoid tissues, and the increased stimulation of DCs by LIGHT can enhance T-DC interaction to contribute to a positive loop of immune responses, leading to strong autoimmunity or antitumor immunity.

	Acknowledgments

 
We appreciate Jason Cyster for providing plt mice, and Sarah Blink and Youjin Lee for their comments and editing of the manuscripts. We acknowledge help from the National Cell Culture Center with the production of LTR-Ig.

	Disclosures

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The authors have no financial conflict of interest.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants R01AI062026, R01DK58897, and P01CA09296-01 (to Y.-X.F.). K.D.K. is supported in part by the Korea Science and Engineering Foudation.

² Y.-G.W. and K.D.K. share first authorship.

³ Address correspondence and reprint requests to Dr. Yang-Xin Fu, Department of Pathology, University of Chicago, Chicago, IL 60637. E-mail address: yfu{at}uchicago.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; HVEM, herpes virus entry mediator; IBD, inflammatory bowel disease; LIGHT, homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for HVEM on T cells; LT, lymphotoxin; LTR, LT receptor; Tg, transgenic; wt, wild type.

Received for publication May 26, 2005. Accepted for publication September 1, 2005.

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Top Abstract Introduction Materials and Methods Results Discussion Disclosures References

 

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