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

Department of Pediatrics, University of Wisconsin–Madison, Madison, Wisconsin, United States
The Journal of Immunology (Impact Factor: 4.92). 01/2007; 177(11):7750-60. DOI: 10.4049/jimmunol.177.11.7750
Source: PubMed


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.

  • Source
    • "Additionally, CNS antigens readily accumulate in the cervical lymph nodes [123]. Further, when labeled DCs are injected into the brain parenchyma, they are able to travel to cervical lymph nodes and elicit an immune response [124]. Indeed, in an elegant study, the immune response to a foreign antigen injected in the brain was shown to be initiated in the cervical lymph node, with activated T-cells then traveling to the CNS [122]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is a devastating neurological disease that predominantly affects young adults resulting in severe personal and economic impact. The majority of therapies for this disease were developed in, or are beneficial in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. While known to target adaptive anti-CNS immune responses, they also target, the innate immune arm. This mini-review focuses on the role of dendritic cells (DCs), the professional antigen presenting cells of the innate immune system. The evidence for a role for DCs in the appropriate regulation of anti-CNS autoimmune responses and their role in MS disease susceptibility and possible therapeutic utility are discussed. Additionally, the current controversy regarding the evidence for the presence of functional DCs in the normal CNS is reviewed. Furthermore, the role of CNS DCs and potential routes of their intercourse between the CNS and cervical lymph nodes are considered. Finally, the future role that this nexus between the CNS and the cervical lymph nodes might play in site directed molecular and cellular therapy for MS is outlined.
    Full-text · Article · Dec 2012 · International Journal of Molecular Sciences
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2012 · Advances in Experimental Medicine and Biology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Mar 2010 · European Journal of Neuroscience
Show more