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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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    • "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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    • "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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