Dendritic Cells Amplify T Cell-Mediated Immune Responses in the Central Nervous System

Cellular and Molecular Pathology Graduate Program, Department of Pathology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
The Journal of Immunology (Impact Factor: 5.36). 01/2007; 177(11):7750-60. DOI: 10.4049/jimmunol.177.11.7750
Source: PubMed

ABSTRACT Neuroinflammation often starts with the invasion of T lymphocytes into the CNS leading to recruitment of macrophages and amplification of inflammation. In this study, we show that dendritic cells (DCs) facilitate T-T cell help in the CNS and contribute to the amplification of local neuroinflammation. We adoptively transferred defined amounts of naive TCR-transgenic (TCR) recombination-activating gene-1-deficient T cells into another TCR-transgenic mouse strain expressing different Ag specificity. Following adoptive transfers, we coinjected DCs that presented one or multiple Ags into the brain and followed the activation of T cells with defined specificities simultaneously. Injection of DCs presenting both Ags simultaneously led to significantly higher infiltration of T cells into the brain compared with injection of a mixture of DCs pulsed with two Ags separately. DCs mediated either cooperative or competitive interactions between T cell populations with different specificities depending upon their MHC-restricting element usage. These results suggest that DC-mediated cooperation between brain-infiltrating T cells of different Ag specificities in the CNS plays an important role in regulation of neuroinflammation. This work also implies that blocking Ag-specific responses may block not only the targeted specificities, but may also effectively block their cooperative assistance to other T cells. Therefore, these data justify more attention to Ag-specific therapeutic approaches for neuroinflammation.

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    • "injection of two antigens into TCR transgenic mice with T-cells specific for one of the antigens, transfer of T-cells specific for the other antigen promoted recruitment of host T-cells to the CNS—an effect not observed when antigens were injected in spatially distinct compartments. This could be blocked by retrovirally inhibiting CD40L or IL-2 expression in the donor T-cells, suggesting that perhaps paracrine IL-2 signaling between closely associated T-cells as well as CD40L-induced DC activation may be important for T-cell–T-cell cooperation (Karman et al. 2006). Recently, we generated transgenic mice that express OVA 257–264 -OVA 323–339 -PCC 88–104 T-cell epitopes in oligodendrocytes (manuscript in preparation). "
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    ABSTRACT: Dendritic cells (DCs) are a heterogeneous group of professional antigen presenting cells that lie in a nexus between innate and adaptive immunity because they recognize and respond to danger signals and subsequently initiate and regulate effector T-cell responses. Initially thought to be absent from the CNS, both plasmacytoid and conventional DCs as well as DC precursors have recently been detected in several CNS compartments where they are seemingly poised for responding to injury and pathogens. Additionally, monocyte-derived DCs rapidly accumulate in the inflamed CNS where they, along with other DC subsets, may function to locally regulate effector T-cells and/or carry antigens to CNS-draining cervical lymph nodes. In this review we highlight recent research showing that (a) distinct inflammatory stimuli differentially recruit DC subsets to the CNS; (b) DC recruitment across the blood-brain barrier (BBB) is regulated by adhesion molecules, growth factors, and chemokines; and (c) DCs positively or negatively regulate immune responses in the CNS.
    Advances in Experimental Medicine and Biology 01/2012; 946:309-33. DOI:10.1007/978-1-4614-0106-3_18 · 2.01 Impact Factor
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    • "Flow cytometry thus demonstrated strong acquisition of the dendritic cell receptor CD11c ⁄ Itgax (Chiu et al., 2008). The cluster of Cxcl10-expressing cells may serve as foci for interactions between antigen-presenting Itgax + cells and populations of T-cells (Karman et al., 2006). In conclusion, chemokines such as Cxcl10 are putative targets for pharmacological intervention as they mediate cell signals among inflammatory cells, e.g. "
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    ABSTRACT: Traumatic brain injury (TBI) in the mouse results in the rapid appearance of scattered clusters of cells expressing the chemokine Cxcl10 in cortical and subcortical areas. To extend the observation of this unique pattern, we used neuropathological mouse models using quantitative reverse transcriptase-polymerase chain reaction, gene array analysis, in-situ hybridization and flow cytometry. As for TBI, cell clusters of 150-200 mum expressing Cxcl10 characterize the cerebral cortex of mice carrying a transgene encoding the Swedish mutation of amyloid precursor protein, a model of amyloid Alzheimer pathology. The same pattern was found in experimental autoimmune encephalomyelitis in mice modelling multiple sclerosis. In contrast, mice carrying a SOD1(G93A) mutant mimicking amyotrophic lateral sclerosis pathology lacked such cell clusters in the cerebral cortex, whereas clusters appeared in the brainstem and spinal cord. Mice homozygous for a null mutation of the Cxcl10 gene did not show detectable levels of Cxcl10 transcript after TBI, confirming the quantitative reverse transcriptase-polymerase chain reaction and in-situ hybridization signals. Moreover, unbiased microarray expression analysis showed that Cxcl10 was among 112 transcripts in the neocortex upregulated at least threefold in both TBI and ageing TgSwe mice, many of them involved in inflammation. The identity of the Cxcl10(+) cells remains unclear but flow cytometry showed increased numbers of activated microglia/macrophages as well as myeloid dendritic cells in the TBI and experimental autoimmune encephalomyelitis models. It is concluded that the Cxcl10(+) cells appear in the inflamed central nervous system and may represent a novel population of cells that it may be possible to target pharmacologically in a broad range of neurodegenerative conditions.
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    • "Most research fails to convincingly demonstrate the presence of DC in naive brain parenchyma (Lauterbach et al., 2006; Matyszak and Perry, 1996; Perry, 1998; Serafini et al., 2000), although they are readily detected in perivascular spaces, cerebrospinal fluid, and areas unprotected by the blood–brain barrier (BBB) (Bailey et al., 2007; Fischer and Reichmann, 2001; Karman et al., 2006; Lauterbach et al., 2006; Matyszak and Perry, 1996; McMenamin, 1999; Miller et al., 2007; Newman et al., 2005; Perry, 1998; Serafini et al., 2000; Serot et al., 1997, 1998, 2000). Only a handful of recent studies, such as those by Fabry et al. and Bulloch et al. (Bulloch et al., 2008; Karman et al., 2006), have demonstrated DCs in the naive CNS parenchyma. These studies further indicate that either resident or infiltrating DCs provide APC function essential for propagation of innate and adaptive immunity in the CNS. "
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    ABSTRACT: Intranasal application of vesicular stomatitis virus (VSV) causes acute infection of the central nervous system (CNS). However, VSV encephalitis is not invariably fatal, suggesting that the CNS may contain a professional antigen-presenting cell (APC) capable of inducing or propagating a protective antiviral immune response. To examine this possibility, we first characterized the cellular elements that infiltrate the brain as well as the activation status of resident microglia in the brains of normal and transgenic mice acutely ablated of peripheral dendritic cells (DCs) in vivo. VSV encephalitis was characterized by a pronounced infiltrate of myeloid cells (CD45(high)CD11b(+)) and CD8(+) T cells containing a subset that was specific for the immunodominant VSV nuclear protein epitope. This T cell response correlated temporally with a rapid and sustained upregulation of MHC class I expression on microglia, whereas class II expression was markedly delayed. Ablation of peripheral DCs profoundly inhibited the inflammatory response as well as infiltration of virus-specific CD8(+) T cells. Unexpectedly, the VSV-induced interferon-gamma (IFN-gamma) response in the CNS remained intact in DC-deficient mice. Thus, both the inflammatory and certain components of the adaptive primary antiviral immune response in the CNS are dependent on peripheral DCs in vivo.
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