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The Journal of Immunology, 2007, 178, 6695 -6699
Copyright © 2007 by The American Association of Immunologists, Inc.
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Cutting Edge: CNS CD11c+ Cells from Mice with Encephalomyelitis Polarize Th17 cells and Support CD25+CD4+ T cell-Mediated Immunosuppression, Suggesting Dual Roles in the Disease Process1

Pratima Deshpande*, Irah L. King{dagger} and Benjamin M. Segal2,*,{ddagger}

* Department of Microbiology and Immunology, {dagger} Interdepartmental Graduate Program in Neuroscience, and {ddagger} Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
CD11c+ dendritic cells (DCs) are a prominent component of CNS infiltrates in mice with experimental autoimmune encephalomyelitis. However, their role in immunopathogenesis is controversial. In this study, we report that they originate from peripheral hemopoietic cells and exhibit diverse functions that change during the course of acute disease. CNS DCs stimulate naive T cells to proliferate and polarize Th17 responses when harvested shortly following disease onset but are relatively inefficient APC by the time of peak disability. Conversely, they can support CD4+CD25+ T cell-mediated immunosuppression early during experimental autoimmune encephalomyelitis. Such paradoxical functions might reflect dual roles of CNS DCs in promoting local inflammation while setting the stage for remission.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Experimental autoimmune encephalomyelitis (EAE)3 is an inflammatory demyelinating disease of the CNS that is widely used as an animal model of multiple sclerosis (MS). The clinical manifestation of EAE is dependent upon reactivation of myelin-specific CD4+ T cells once they cross the blood-brain barrier (1). According to the concept of epitope spreading, naive T cells specific for novel myelin Ags are primed within the CNS and drive disease relapse or progression (2). In contrast, certain APC subsets anergize or delete myelin-specific T cells during cognate interactions and could potentially limit the severity and/or duration of clinical EAE in vivo (3). Hence, the frequency, distribution, and phenotype of CNS APCs are critical factors in the induction as well as the remission of autoimmune demyelinating diseases.

Despite their importance in initiating and perpetuating adaptive immune responses in the periphery, CD11c+ dendritic cells (DCs) were previously assumed not to be important in neuroinflammation because they are absent from the CNS parenchyma during homeostasis (4). The CNS is one of the few tissues bereft of a lymphatic vasculature capable of supporting DC trafficking. Nevertheless, several recent studies have demonstrated that CD11c+ leukocytes with morphological characteristics of DCs are prominent components of CNS infiltrates in neuroinflammatory states including EAE and MS (5, 6). Some studies suggest that these cells might be particularly efficient in supporting the activation and effector functions of encephalitogenic T cells, while others indicate that they are incompetent in priming naive as well as in expanding memory myelin-specific T cells (5, 6, 7). In light of this controversy, we assessed the cell surface and functional characteristics of CNS CD11c+ cells at EAE onset and peak and compared them to those of CD11c–CD11b+ macrophages/microglia (the other major myeloid subset in EAE lesions) as well as splenic and bone marrow-derived DCs (BMDCs).


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Mice

Wild-type and CD45.1 congenic C57BL/6 mice were purchased from National Cancer Institute-Frederick (Frederick, MD). C57BL/6-Tg (Tcra2D2, Tcrb2D2)1Kuch/J mice (transgenic for the TCR V{alpha}3.2 and Vbeta11 chains reactive to myelin oligodendrocyte glycoprotein (MOG)35–55), commonly known as 2D2 mice, were a gift from Dr. V. Kuchroo (Harvard Medical School, Boston, MA) (8). Experiments were performed using University Committee on Animal Resources-approved protocols.

Reagents

MOG35–55 (MEVGWYRSPFSRVVHLYRNGK) was synthesized by Macromolecular Resources and purified by HPLC. Oligodeoxynucleotides (ODN) were phosphorothioate-modified to increase their resistance to nuclease degradation (Operon Technologies). The sequences were 5'-ATAATCGACGTTCAAGCAAG-3' for CpG ODN (CpG1760) and 5'-ATAATAGAGCTTCAAGCAAG-3' for control ODN (CpG1908).

Abs/fusion proteins used for FACS and whole-mount immunofluorescence were purchased from BD Biosciences except for IgG 2a, {kappa}-APC (eBioscience).

Generation of bone marrow chimeras

C57BL/6 bone marrow cells (10 x 106) were injected into the tail veins of lethally irradiated (1000 rad) CD45.1 congenic hosts. In all cases, the reconstitution efficiency of CD11b+ cells exceeded 95% as assessed by flow cytometry at 5 wk after irradiation.

Induction and evaluation of EAE

Mice were immunized with MOG35–55 (150 µg) in CFA (5 mg/ml heat-killed Mycobacterium tuberculosis H37Ra; v/v) by s.c. injection at four sites over the flanks. Bordetella pertussis toxin (List Laboratories) was injected i.p. (2 ng/mouse) on days 0 and 2. Mice were observed for signs of EAE on a daily basis and graded on a standard scale as previously described (9).

CD4+ T cell and myeloid subset purification/preparation

CD4+ T cells were purified from lymph node cells with CD4 T cell enrichment columns (R & D Systems). CD11c+ cells were purified from splenocytes with anti-CD11c microbeads (Miltenyi Biotec). CD11b+CD11c– and CD11c+ cells were FACS sorted from CNS mononuclear cell (MNC) fractions, as were CD4+CD62Lhigh cells from 2D2 splenocytes. All isolated cells were 93–98% pure. BMDCs were induced by culture with GM-CSF and IL-4 (10).

Cell cultures

Myeloid cells were cultured in 24-well plates (2.5 x 105 cells/ml) with either anti-CD40 mAb (FGK45; (11)), isotype matched rat IgG (5 µg/ml), CpG1760, or control ODN (100 nM). Naive 2D2 cells or MOG-primed CD4+ T cells (2 x 105 cells/well) were cultured with APCs (105 cells/well) in the presence or absence of MOG35–55 (50 µg/ml).

Cytokine ELISA

All cytokines were quantified using a sandwich ELISA technique based on noncompeting pairs of Abs. Capture and detection mAbs were obtained from BD Biosciences except for the anti-IL-23 p19 mAb (gift of J. Benson, Centocor).

Whole-mount immunofluorescence

Spinal cord sections (3 x 2 mm) were stained with labeled mAbs and viewed under a fluorescent microscope (Olympus BX40F) as previously described (9). Background staining with isotype-matched control mAbs was minimal.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
CD11c+ cells accumulate in EAE lesions and form aggregates with CD4+ T cells

In the initial experiments, mice were sacrificed shortly after the onset of clinical EAE to analyze CNS CD11c+ cells and other APC subsets at a time point when local T cell activation is driving the development of inflammatory infiltrates. In repeated experiments CD11c+CD11b+ cells, consistent with myeloid DCs, comprised between 16 and 25% of live CNS mononuclear cells as determined by flow cytometric analysis (Fig. 1A, upper left panel). By contrast, CD11c+CD11b– cells were scarce (2–8%); those detected expressed either CD8{alpha} or Gr-1, indicative of alternative DC subsets (P. Deshpande and B. Segal, unpublished observations). The majority of the remaining cells were CD11c–CD11b+ macrophages/microglia (20–50%) and CD4+ T cells (20–30%).


Figure 1
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  		FIGURE 1. CD11c+CD11b+ cells in the CNS of mice with EAE express a mature phenotype and aggregate with CD4+ T cells. A, Spinal cord MNCs were isolated from mice with EAE, stained with mAbs specific for CD11b and CD11c, and subjected to flow cytometry (upper left panel). In parallel studies, the localization of CD11c+ (yellow stain), CD11b+ (green, lower right panel), and CD4+ (red, upper right panel) cells in spinal cord sections from mice with EAE was assessed by whole-mount immunofluorescence. Blood vessels were visualized via CD31 expression (green, upper right panel). Original magnification for images was x20. Isotype-matched Abs showed no detectable background signal (data not shown). B, Spinal cord MNCs (upper and middle panels) and splenocytes (lower panels) harvested from mice shortly following EAE onset were stained with mAbs for CD11b, CD11c, and either CD80, CD86, MHC II, or CCR7 (heavy line) or isotype matched control mAbs (gray line) before analysis by flow cytometry. Cell surface molecule expression was assessed by gating on CD11c+ (upper and lower panels) and CD11c–CD11b+ (middle panels) subsets. C, Bone marrow chimeras were constructed by injecting CD45.1+ congenic bone marrow cells into lethally irradiated CD45.2+C57BL/6 hosts. Following reconstitution, spinal cords were harvested and pooled for the isolation of CNS MNCs (primarily consisting of microglia). CNS MNCs were subsequently analyzed by FACS for the expression of CD45.1 (donor) and CD45.2 (host) alleles on CD11b+ cells. D, Reconstituted chimeric mice were immunized with MOG35–55 in CFA to induce EAE. Spinal cord mononuclear cells were harvested at peak disease and analyzed by FACS for expression of CD45 alleles on CD11c+ and CD11b+ cells. These experiments were repeated four or more times with similar results.

 
CNS CD11c+CD11b+ cells expressed relatively high levels of MHC class II, CD80, and CD86 at EAE onset, comparable to CD11c+ splenocytes harvested from the same animals (Fig. 1B). A significant subset (40–50%) reproducibly expressed the chemokine receptor CCR7. This cell surface profile is consistent with a mature status and APC competence. CD11c–CD11b+ macrophages/microglia also expressed MHC class II and key costimulatory molecules, although generally to a lesser extent (with regard to the percentage of positive cells and/or cell surface density) than their CD11c+ counterparts.

Next, we analyzed intact EAE lesions by whole-mount immunofluorescence to assess the spatial relationship between DC-like cells and T cells. Consistent with the flow cytometry data, virtually all CD11c+ cells coexpressed the myeloid marker CD11b (Fig. 1A, lower panels). CD11c+ cells formed clusters with CD4+ T cells adjacent to CD31+ blood vessels (Fig. 1A, upper right panel). Hence, CNS myeloid DC-like cells are well positioned to activate myelin-specific T cells in situ.

CNS DCs originate from the peripheral pool of circulating leukocytes

Microglia can exhibit DC-like morphology, phenotype, and T cell-activating properties following the activation of CD40 or TLRs in vitro (5). To distinguish whether CD11c+ cells in EAE lesions arise from CNS resident microglia or circulating hemopoietic cells, we constructed bone marrow chimeras with CD45.1 congenic donors and CD45.2 hosts. As expected, the vast majority of CD11b+ cells in spinal cord mononuclear fractions from unimmunized chimeras, representative of microglia, were of host origin (Fig. 1C). In contrast, >95% of CD11c+ and CD11b+ cells in spinal cord mononuclear fractions from MOG-immunized mice sacrificed at peak EAE were of donor origin, suggesting that these cells or their precursors infiltrated the CNS from the circulation (Fig. 1D).

CNS CD11c+ cells from early EAE infiltrates stimulate naive MOG-specific T cells to divide

Mature myeloid DCs in bone marrow, lymphoid organs, and other tissues external to the CNS are distinguished by their ability to prime naive T cells. However, there is conflicting data regarding the outcome of interactions between CNS DCs and CD4+ T cells (2, 5, 6, 7). To investigate the biological properties of CNS DCs in our experimental system, we purified CD11c+ cells from spinal cords within several days of EAE onset and cocultured them with CFSE-labeled, naive (CD62L+CD25–CD44–) MOG-specific CD4+ (2D2) T cells. For comparative purposes, 2D2 cells were cocultured with CNS CD11c–CD11b+ and splenic CD11c+ cells from the same donors in parallel. As shown in Fig. 2, 2D2 cells underwent multiple rounds of division upon culture with MOG-pulsed CNS CD11c+ cells, a response approximating that elicited by CD11c+ splenocytes and exceeding that elicited by T cell-depleted splenocytes. By contrast, relatively few 2D2 cells proliferated upon coculture with CNS CD11c–CD11b+ macrophages and Ag, even at high APC to T cell ratios (Fig. 2, lower panels). A similar pattern was observed when OVA-specific TCR transgenic cells were combined with the same APC populations (not shown).


Figure 2
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  		FIGURE 2. CNS DCs prime naive myelin-specific T cells. CFSE dilution of naive (CD62L+CD44–CD25–) CD4+ 2D2 cells was measured following a 72 h culture with MOG35–55 in the presence of the APC subsets indicated. The APC to T cell ratios were 1:1 (lower panels) and 1:10 (middle panels). The upper panels show the profiles of unstimulated T cells (1:1 ratio). T-dep. Spl., T cell-depleted splenocytes; M{phi}, CD11b+CD11c– macrophage; Spl. DC, splenic CD11c+ DCs.

 
CNS CD11c+ cells express intracellular IL-12 p40 and secrete IL-12 and IL-23 in response to various stimuli

In addition to activating naive CD4+ T cells, peripheral myeloid DCs direct Th lineage commitment via the secretion of polarizing cytokines. Encephalitogenic CD4+ T cells that accumulate in EAE lesions predominantly fall within the Th17 and Th1 subsets (8, 9). The IL-12 p40 monokines IL-12 and IL-23, promote/stabilize Th1 and Th17 differentiation, respectively. Therefore we measured IL-12 and IL-23 production by CNS CD11c+ cells and other APCs in response to various inflammatory stimuli and during cognate interactions with T cells.

Approximately 50% of CD11c+CD11b+ cells and 17% of CD11c–CD11b+ cells expressed intracellular IL-12 p40 when analyzed during the early phases of clinical EAE (Fig. 3A). Both subsets secreted IL-12 and IL-23 heterodimers following short-term stimulation with a CpG-containing ODN, although CD11c+ cells consistently secreted significantly larger quantities (Fig. 3B). CNS CD11c+, but not CD11c–CD11b+, cells secreted IL-12 and IL-23 in response to CD40 ligation. Similarly, CNS CD11c+ cells produced significantly more IL-12 and IL-23 than CNS CD11c–CD11b+ cells during coculture with either naive 2D2 cells or primed polyclonal MOG-specific CD4+ T cells in the presence of Ag (Fig. 3, C and D).


Figure 3
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  		FIGURE 3. CNS-DCs secrete relatively large amounts of IL-12 p40 cytokines. A, MNCs from cords of mice with early EAE were stimulated with CpG1760 or control ODN for 12 h before intracellular cytokine staining with an anti-IL12 p40 mAb and flow cytometry. B, CD11c+ (CNS DC) and CD11c–CD11b+ (CNS M{phi}) cells were sorted from spinal cord MNCs with magnetic beads and cultured with the reagents indicated. IL-12p70, and IL-23 levels were measured at 72 h by ELISA. Splenic CD11c+ cells (Spl. DC) from the same donors and BMDCs served as positive controls. C and D, Cytokine levels were measured following the culture of naive CD62L+ (C) or primed (D) MOG-specific CD4+ T cells with APC subsets with or without the MOG peptide. The data shown are representative of 3–5 independent experiments. T dep. Spl., T cell-depleted splenocytes. *, p < 0.05; comparing CD11c+ and CD11c–CD11b+ subsets.

 
CNS CD11c+ cells support the differentiation of naive myelin-specific CD4+ T cells into Th1 and Th17 cells

To directly compare the relative capacities of CNS APC subsets to direct Th differentiation of autoreactive CD4+ T cells, we measured IL-2, IL-17, IFN-{gamma}, and GM-CSF levels in supernatants from the same cocultures as those illustrated in Fig. 3C. CNS CD11c+ cells were essentially as effective as splenic DC in inducing MOG-specific IFN-{gamma} and GM-CSF production during culture with naive 2D2 cells (Fig. 4A). They also stimulated the naive T cells to secrete substantial quantities of IL-17. In contrast, CNS CD11c–CD11b+ cells induced little if any cytokine production beyond baseline levels. Consistent with the proliferation data shown in Fig. 2, only CD11c+ CNS cells stimulated significant IL-2 secretion.


Figure 4
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  		FIGURE 4. CNS CD11c+ cells polarize and expand Th1 and Th17 cells. A and B CD62L+CD4+ MOG-specific 2D2 T cells were cultured with FACS-sorted APC subpopulations with {square} or without ({blacksquare}) MOG peptide. Cytokine levels were measured in 72-h supernatants by ELISA. The data are representative of 3–5 experiments. *, p < 0.05; **, p < 0.01; and ***, p < 0.005 comparing CD11c+ and CD11c–CD11b+ subsets.

 
Several recent studies indicate that whereas IL-23 stabilizes and/or facilitates the expansion of Th17 cells, IL-6 and TGF-beta induce Th17 differentiation of uncommitted T cells (8). We detected TGF-beta at comparable concentrations across all cocultures, irrespective of APC phenotype or the presence or absence of Ag (Fig. 4B). By contrast, IL-6 was preferentially up-regulated in cultures that contained CNS CD11c+ cells or BMDCs. Hence, IL-6 production may be the pivotal factor that predisposes CNS CD11c+ cells to induce Th17 differentiation.

We also assessed CNS APCs with regard to their ability to reactivate primed myelin-specific T cells. Both CD11c+ and CD11c– myeloid subsets stimulated CD4+ T cells from MOG35–55-immunized mice to secrete IFN-{gamma}, IL-17, and GM-CSF in an Ag-specific manner; the levels of IL-2 and GM-CSF were consistently higher in supernatants from cocultures with CD11c+ cells (data not shown).

CD11c+ cells harvested from the CNS immediately before the remission phase of EAE are relatively inefficient APCs

MOG-induced EAE characteristically follows a monophasic course in C57BL/6 mice, reminiscent of idiopathic transverse myelitis, optic neuritis, and some forms of acute disseminated encephalomyelitis in humans. Little is known about the cellular and molecular events underlying the transition between the active inflammatory and remitting stages of autoimmune demyelination. We questioned whether the CNS CD11c+ subpopulation evolves as acute disease advances, losing T cell stimulatory potency at the peak of clinical disability and thereby curbing the autoimmune response preparatory to the remission phase. To test this hypothesis we analyzed CNS CD11c+ cells for the expression of maturation markers as well as for the ability to activate CD62LhighCD44–CD25– 2D2 T cells when harvested shortly following clinical presentation vs during peak disease. Splenic CD11c+ cells were used as a control APC population. CNS CD11c+ cells harvested on day 18 postimmunization, immediately before the expected onset of remission, expressed relatively low levels of CCR7, CD86, and MHC class II, suggestive of an immature phenotype (Fig. 5B). Furthermore, these cells were clearly and consistently less efficient than the CNS CD11c+ cells harvested during early EAE in stimulating naive myelin-specific T cells to expand (Fig. 5A) or secrete proinflammatory cytokines (data not shown) in vitro.


Figure 5
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  		FIGURE 5. CNS CD11c+ becomes less efficient at activating myelin-specific T cells at peak EAE and supports Treg-mediated suppression after clinical onset. A and B, CNS CD11c+ cells were isolated from mice either shortly following clinical EAE onset (Onset EAE) or during peak disease, immediately before the expected onset of remission (Peak EAE). A, CNS CD11c+ cells (black line) or CD11c+ splenocytes (gray line), isolated at either the onset (left panel) or peak (right panel) of EAE, were cultured with CFSE-labeled, naive MOG-specific 2D2 cells and MOG35–55 as described in Fig. 2. B, Each CNS CD11c+ population was stained with mAbs specific for maturation markers and analyzed by FACS. The experiment was reproduced three times. For a negative control, MOG-specific T cells were cultured with CNS CD11c+ in the absence of Ag (broken line). The data shown are representative of four experiments with similar results. C, CFSE-labeled naive 2D2 T cells were cultured with (black line) or without (gray line) CD45.1+ congenic CD4+CD25+ Tregs and either T cell-depleted splenocytes (T dep Spl.; middle panel) or CNS CD11c+ cells (right panel) at a ratio of one 2D2 cell to one Treg to one APC. As a negative control, 2D2 cells were cultured with Tregs in the absence of APCs (left panel). After 96 h of stimulation with soluble anti-CD3, CFSE dilution was measured in CD45.2+CD4+ gated cells. Experiments were repeated four or more times with similar results. *, p < 0.05.

 
CNS CD11c+ cells support CD25+CD4+ regulatory T cell (Treg)-mediated suppression

In addition to losing optimal T cell stimulatory capacity during disease progression, we considered the possibility that CNS DCs actively engage immunoregulatory pathways earlier in the course to limit the extent of CNS inflammation and to set the stage for subsequent remission. CD25+CD4+ FoxP3+ T cells (Treg) begin accumulating in the CNS before peak disease; depletion of these cells before EAE induction exacerbates severity and delays recovery (12). We questioned whether mature CNS CD11c+ cells could support CD25+CD4+ T cell (Treg)-mediated suppression. It was previously reported that LPS-activated splenic DCs overcome CD25+ Treg-mediated suppression of conventional CD4+ T cells (10, 13). In contrast, we found that Tregs retained their suppressive properties in the presence of CNS CD11c+ cells (Fig. 5C).


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
Our finding that CNS CD11c+ cells undergo functional changes on a population level during the course of acute EAE could explain the discrepancies in the literature regarding the biological properties of these cells (2, 5, 6, 7). At disease onset, clinical EAE progresses rapidly in association with the establishment of CNS infiltrates. Because the neuroinflammatory process is driven by myelin-specific CD4+ Th17 cells (8), it is not surprising that IL-23-producing DCs, the most potent APCs known, are prominent during this stage. However, disability plateaus within several days and diminishes shortly thereafter as the inflammatory infiltrates retract. The data in this paper suggests that the regression of CNS CD11c+ cells from mature Th17-polarizing APCs into an immature phenotype is an integral step in the transition from active neuroinflammation to remission. In addition, previous publications have implicated CD25+CD4+ Treg in the recovery from acute EAE (12). Our finding that CNS CD11c+ cells from mice with EAE are able to support Treg-mediated immunosuppression provides an additional mechanism by which the autoimmune response can be curbed locally in preparation for the remitting phase. In this manner, the DCs that accumulate in the CNS immediately before EAE remission might differ from the DCs that accumulate in other peripheral organs targeted during chronic (nonremitting) autoimmune syndromes (13).

CNS DCs express lower levels of MHC class II and costimulatory molecules at peak disease than at disease onset, providing one possible explanation for their reduced APC potency over time (Fig. 5B). As yet, we have no evidence that they secrete immunosuppressive cytokines (Fig. 4B; data not shown). We have not established whether CNS DCs down-regulate stimulatory functions on an individual basis or whether mature DCs that dominate the infiltrating myeloid population at EAE onset are replaced by immature DCs at peak disease. We found that CNS CD11c+ cells are derived from hemopoietic cells that infiltrate the CNS from the circulation (Fig. 1D). Based on that observation and taking into account the relatively short lifespan of DCs following migration into peripheral tissues, we believe that the latter scenario is most likely. The factors that govern DC differentiation and maturation status within the CNS microenvironment is a topic of continuing interest and research in our laboratory.

There is growing evidence that DCs accumulate in the CNS during autoimmune demyelinating diseases in humans such as MS (6). Therefore, our findings may have relevance regarding the immunopathogenesis and treatment of those disorders. Interventions that accelerate the conversion of CNS DCs from an activated to an immature state might be therapeutically useful in MS.


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
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References
 
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 by National Multiple Sclerosis Society Grant RG 3866-A-3 and National Institutes of Health Grant NS047687-01A1. Back

2 Address correspondence and reprint requests to Dr. Benjamin M. Segal, Department of Neurology/Neuroimmunology, University of Rochester School of Medicine, 601 Elmwood Avenue, Box 605, Rochester, NY 14642. E-mail address: Benjamin_Segal{at}urmc.rochester.edu Back

3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; DC, dendritic cell; BMDC, bone marrow DC; MS, multiple sclerosis; MNC, mononuclear cell; MOG, myelin oligodendrocyte glycoprotein; ODN, oligodeoxynucleotide; Treg, CD4+CD25+ regulatory T cell. Back

Received for publication February 20, 2007. Accepted for publication March 27, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

  1. Kawakami, N., S. Lassmann, Z. Li, F. Odoardi, T. Ritter, T. Ziemssen, W. E. Klinkert, J. W. Ellwart, M. Bradl, K. Krivacic, et al 2004. The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis. J. Exp. Med. 199: 185-197. [Abstract/Free Full Text]
  2. McMahon, E. J., S. L. Bailey, C. V. Castenada, H. Waldner, S. D. Miller. 2005. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat. Med. 11: 335-339. [Medline]
  3. Hawiger, D., R. F. Masilamani, E. Bettelli, V. K. Kuchroo, M. C. Nussenzweig. 2004. Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. Immunity 20: 695-705. [Medline]
  4. Hart, D. N., J. W. Fabre. 1981. Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J. Exp. Med. 154: 347-361. [Abstract/Free Full Text]
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  6. Greter, M., F. L. Heppner, M. P. Lemos, B. M. Odermatt, N. Goebels, T. Laufer, R. J. Noelle, B. Becher. 2005. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11: 328-334. [Medline]
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  9. Deshpande, P., I. L. King, B. M. Segal. 2006. IL-12 driven upregulation of P-selectin ligand on myelin-specific T cells is a critical step in an animal model of autoimmune demyelination. J. Neuroimmunol. 173: 35-44. [Medline]
  10. Pasare, C., R. Medzhitov. 2003. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299: 1033-1036. [Abstract/Free Full Text]
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