Intracerebral Dendritic Cells Critically Modulate Encephalitogenic versus Regulatory Immune Responses in the CNS

Zozulya, Alla L.; Ortler, Sonja; Lee, JangEun; Weidenfeller, Christian; Sándor, Mátyás; Wiendl, Heinz; Fábry, Zsuzsanna

doi:10.1523/jneurosci.2199-08.2009

Cited by 65 publications

(80 citation statements)

References 56 publications

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“…Third, it was reported that eradicating part of the myeloid compartment or blocking specific signaling capacity of DCs/APCs (in the periphery as well as in the CNS) reduces the severity of EAE (44)(45)(46). Fourth, intracerebral application of MOG-loaded DCs results in exacerbation of EAE (47). Finally, our own data show that TNF-a secretion and NO production after LPS stimulation was similar in wild-type and ADAPdeficient microglia cells.…”

Section: Discussionmentioning

confidence: 62%

T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice

Engelmann

Togni

Thielitz

et al. 2013

The Journal of Immunology

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The adhesion- and degranulation-promoting adaptor protein (ADAP), expressed in T cells, myeloid cells, and platelets, is known to regulate receptor-mediated inside-out signaling leading to integrin activation and adhesion. In this study, we demonstrate that, upon induction of active experimental autoimmune encephalomyelitis (EAE) by immunization with the myelin oligodendrocyte glycoprotein35–55 peptide, ADAP-deficient mice developed a significantly milder clinical course of EAE and showed markedly less inflammatory infiltrates in the CNS than wild-type mice. Moreover, ADAP-deficient recipients failed to induce EAE after adoptive transfer of myelin oligodendrocyte glycoprotein–specific TCR-transgenic T cells (2D2 T cells). In addition, ex vivo fully activated 2D2 T cells induced significantly less severe EAE in ADAP-deficient recipients. The ameliorated disease in the absence of ADAP was not due to expansion or deletion of a particular T cell subset but rather because of a strong reduction of all inflammatory leukocyte populations invading the CNS. Monitoring the adoptively transferred 2D2 T cells over time demonstrated that they accumulated within the lymph nodes of ADAP-deficient hosts. Importantly, transfer of complete wild-type bone marrow or even bone marrow of 2D2 TCR–transgenic mice was unable to reconstitute EAE in the ADAP-deficient animals, indicating that the milder EAE was dependent on (a) radio-resistant nonhematopoietic cell population(s). Two-photon microscopy of lymph node explants revealed that adoptively transferred lymphocytes accumulated at lymphatic vessels in the lymph nodes of ADAP-deficient mice. Thus, our data identify a T cell–independent mechanism of EAE modulation in ADAP-deficient mice.

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Section: Discussionmentioning

confidence: 62%

T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice

Engelmann

Togni

Thielitz

et al. 2013

The Journal of Immunology

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“…Earlier studies showed that the presence and function of DCs in the CNS correlates with EAE severity (6,8). These professional APCs have been suggested to participate in restimulation of myelin-specific CD4 + T cells in the CNS (5,7,39,40).…”

Section: Discussionmentioning

confidence: 99%

“…In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4)(5)(6)(7)(8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.…”

mentioning

confidence: 99%

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Poppensieker

Otte

Schürmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4 −/− mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4 −/− mice, indicating that CCR4 + DCs are cellular mediators of EAE development. Mechanistically, CCR4 −/− DCs were less efficient in GM-CSF and IL-23 production and also T H -17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4 −/− mice, whereas intracerebral inoculation using IL-23 −/− DCs or GM-CSF −/− DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.chemokines | neuroinflammation M ultiple sclerosis (MS) is a chronic demyelinating disease of the human CNS (1). Experimental autoimmune encephalomyelitis (EAE), the animal model of MS, is mediated by myelin-specific CD4 + T cells activated by professional antigenpresenting cells (APCs) in peripheral lymphoid tissues (2, 3). In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4-8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.Chemokines and their G protein-coupled receptors are key regulators of leukocyte trafficking (9, 10). The CC chemokine receptor 4 (CCR4) is the cognate receptor for the CC chemokines CCL17 and CCL22, and is expressed on functionally distinct subsets of T cells, including activated T cells, T H 2 cells, and Treg cells. CCR4 has also been found on platelets, NK cells, macrophages, and DCs (11-15). DCs are important cellular sources for CCL17 and, in concert with macrophages, produce CCL22 during both homeostasis and inflammation (16,17). Different studies have suggested a critical role for CCR4 in the pathogenesis of EAE and MS. For example, elevated levels of the CCR4 ligands CCL17 or CCL22 have been found in the cerebrospinal fluid of MS patients (18-20). CCL22 protein has been identified in CNS-infiltrating leukocytes and microglia of EAE-induced mice, and CCR4 is expressed by invading leukocyte subsets (21,22). However, it rema...

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“…DCs found within MS lesions have been shown to be functionally abnormal [61]. Further, intra-cerebral DCs were found to critically modulate encephalitogenic versus regulatory immune responses in CNS of EAE mice, an animal model of MS and hence considered to be rate-limiting factor for neuroinflammation [62].…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

Dendritic Cells in Autoimmune Diseases

Maddur¹,

Vani²,

Dimitrov³

et al. 2010

Open Arth J

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Dendritic cells (DCs) are professional antigen presenting cells, which play a crucial role both in maintaining immune tolerance and in inducing adaptive immune responses. Therefore, DCs are the most sought in inciting autoimmunity and its sustenance to autoimmune diseases. The emerging knowledge of the importance of DCs, DC-derived cytokines, and intracellular signal transduction pathways in mediating autoimmune diseases and in creating an inflammatory environment provides a rationale for pursuing strategies to block these inflammatory pathways for therapeutic purposes.

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Intracerebral Dendritic Cells Critically Modulate Encephalitogenic versus Regulatory Immune Responses in the CNS

Cited by 65 publications

References 56 publications

T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice

T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice

CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells

Dendritic Cells in Autoimmune Diseases

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