CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system

Institute of Clinical Neuroanatomy, Johann Wolfgang Goethe-University, 60590 Frankfurt/Main, Germany.
Acta Neuropathologica (Impact Factor: 10.76). 11/2010; 121(4):445-58. DOI: 10.1007/s00401-010-0774-y
Source: PubMed


Recent studies demonstrated that primary immune responses can be induced within the brain depending on vessel-associated cells expressing markers of dendritic cells (DC). Using mice transcribing the green fluorescent protein (GFP) under the promoter of the DC marker CD11c, we determined the distribution, phenotype, and source of CD11c+ cells in non-diseased brains. Predilection areas of multiple sclerosis (MS) lesions (periventricular area, adjacent fibre tracts, and optical nerve) were preferentially populated by CD11c+ cells. Most CD11c+ cells were located within the juxtavascular parenchyma rather than the perivascular spaces. Virtually all CD11c+ cells co-expressed ionized calcium-binding adaptor molecule 1 (IBA-1), CD11b, while detectable levels of major histocompatibility complex II (MHC-II) in non-diseased mice was restricted to CD11c+ cells of the choroid plexus. Cellular processes project into the glia limitans which may allow transport and/or presentation of intraparenchymal antigens to extravasated T cells in perivascular spaces. In chimeric mice bearing CD11c-GFP bone marrow, fluorescent cells appeared in the CNS between 8 and 12 weeks after transplantation. In organotypic slice cultures from CD11c-GFP mice, the number of fluorescent cells strongly increased within 72 h. Strikingly, using anti-CD209, an established marker for human DC, a similar population was detected in human brains. Thus, we show for the first time that CD11c+ cells can not only be recruited from the blood into the parenchyma, but also develop from an intraneural precursor in situ. Dysbalance in their recruitment/development may be an initial step in the pathogenesis of chronic (autoimmune) neuroinflammatory diseases such as MS.

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    • "In this regard, several lines of evidence, including in vitro studies (Fischer and Reichmann, 2001;Butovsky et al., 2007) and neuroinflammatory situations such as ischemia (Kostulas et al., 2002) and EAE (Fischer and Reichmann, 2001;Almolda et al., 2011b;Wlodarczyk et al., 2014), support the hypothesis that parenchymal DCs are derived from the differentiation of local cells, probably microglia, on the basis that the expression of some of the surface antigens commonly used for the identification of DCs, such as CD11c, MHCII and CD86, are found in activated microglial cells. In addition, a study using the CD11c-GFP mouse, which expresses the GFP protein under the control of the CD11c promoter, the pan-marker of DCs, has reported the presence of CD11c+ cells not only in the choroid plexuses and perivascular space but also in the juxtavascular parenchyma of non-lesioned CNS (Prodinger et al., 2010). Interestingly, these authors found that almost all CD11c+ cells in the juxtavascular parenchyma presented markers of microglial cells such as Iba1 and CD11b, indicating that, presumably, a subpopulation of microglial cells is able to express DC markers in steady-state conditions. "
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    ABSTRACT: The infiltration of immune cells in the central nervous system is a common hallmark in different neuroinflammatory conditions. Accumulating evidence indicates that resident glial cells can establish a cross-talk with infiltrated immune cells, including T-cells, regulating their recruitment, activation and function within the CNS. Although the healthy CNS has been thought to be devoid of professional dendritic cells (DCs), numerous studies have reported the presence of a population of DCs in specific locations such as the meninges, choroid plexuses and the perivascular space. Moreover, the infiltration of DC precursors during neuroinflammatory situations has been proposed, suggesting a putative role of these cells in the regulation of lymphocyte activity within the CNS. On the other hand, under specific circumstances, microglial cells are able to acquire a phenotype of DC expressing a wide range of molecules that equip these cells with all the necessary machinery for communication with T-cells. In this review, we summarize the current knowledge on the expression of molecules involved in the cross-talk with T-cells in both microglial cells and DCs and discuss the potential contribution of each of these cell populations on the control of lymphocyte function within the CNS.
    Full-text · Article · Nov 2015 · Frontiers in Cellular Neuroscience
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    • "Recent data obtained with transgenic mouse lines confirm the existence of resident bDCs in the nondiseased mouse brain; for example, bDCs from transgenic CD11c-EYFP mice identified by EYFP expression colocalize with other immune markers commonly associated with DCs and microglia/macrophages (Axtell and Steinman, 2009; Bulloch et al., 2008; D'Agostino et al., 2012). Furthermore, bDC CD11c 1 cells have been identified in CD11c-GFP mice (Jung et al., 2002; Prodinger et al., 2011). In the periphery, DCs are the antigen presenting cells (APC) that mediate T-cell immunity and tolerance . "
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    ABSTRACT: The role and different origin of brain myeloid cells in the brain is central to understanding how the central nervous system (CNS) responds to injury. C-type lectin receptor family 9, member A (DNGR-1/CLEC9A) is a marker of specific DC subsets that share functional similarities, such as CD8α(+) DCs in lymphoid tissues and CD103(+) CD11b(low) DCs in peripheral tissues. Here, we analyzed the presence of DNGR-1 in DCs present in the mouse brain (bDCs). Dngr-1/Clec9a mRNA is expressed mainly in the meningeal membranes and choroid plexus (m/Ch), and its expression is enhanced by fms-like tyrosine kinase 3 ligand (Flt3L), a cytokine involved in DC homeostasis. Using Clec9a(egfp/egfp) mice, we show that Flt3L induces accumulation of DNGR-1-EGFP(+) cells in the brain m/Ch. Most of these cells also express major histocompatibility complex class II (MHCII) molecules. We also observed an increase in specific markers of cDC CD8α+ cells such as Batf-3 and Irf-8, but not of costimulatory molecules such as Cd80 and Cd86, indicating an immature phenotype for these bDCs in the noninjured brain. The presence of DNGR-1 in the brain provides a potential marker for the study of this specific brain cell subset. Knowledge and targeting of brain antigen presenting cells (APCs) has implications for the fight against brain diseases such as neuroinflammation-based neurodegenerative diseases, microbe-induced encephalitis, and brain tumors such as gliomas. GLIA 2015. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Jul 2015 · Glia
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    • "In previous studies Greter et al . demonstrated the exis - tence of vessel - associated CD11c - positive cells , which appeared to be located in pv spaces ( Greter et al . , 2005 ) . Fur - thermore , using fluorescence and electron microscopy our group identified an intraparenchymal population of CD11c - positive cells ( Prodinger et al . , 2011 ) , which express the mac - rophage marker IBA - 1 and CD11b . In continuation of our previous work , the current study demonstrates that cells expressing a microglial phenotype ( CD45 int , CD11b ) contain a distinct subpopulation expressing CD11c . This is in line with previous studies confirming the existence of CD11c - positive cell"
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    ABSTRACT: The brain's immune privilege has been also attributed to the lack of dendritic cells (DC) within its parenchyma and the adjacent meninges, an assumption, which implies maintenance of antigens rather than their presentation in lymphoid organs. Using mice transcribing the green fluorescent protein under the promoter of the DC marker CD11c (itgax), we identified a juxtavascular population of cells expressing this DC marker and demonstrated their origin from bone marrow and local microglia. We now phenotypically compared this population with CD11c/CD45 double-positive cells from lung, liver, and spleen in healthy mice using seven-color flow cytometry. We identified unique, site-specific expression patterns of F4/80, CD80, CD86, CX3CR1, CCR2, FLT3, CD103, and MHC-II. Furthermore, we observed the two known CD45-positive populations (CD45(high) and CD45(int) ) in the brain, whereas liver, lung, and spleen exhibited a homogeneous CD45(high) population. CD11c-positive microglia lacked MHC-II expression and CD45(high) /CD11c-positive cells from the brain have a lower percentage of MHC-II-positive cells. To test whether phenotypical differences are fixed by origin or specifically develop due to environmental factors, we transplanted brain and spleen mononuclear cells on organotypic slice cultures from brain (OHSC) and spleen (OSSC). We demonstrate that adaption and ramification of MHC-II-positive splenocytes is paralleled by down-regulation of MHC-II, whereas brain-derived mononuclear cells neither ramified nor up-regulated MHC-II in OSSCs. Thus, brain-derived mononuclear cells maintain their MHC-II-negative phenotype within the environment of an immune organ. Intraparenchymal CD11c-positive cells share immunophenotypical characteristics of DCs from other organs but remain unique for their low MHC-II expression. GLIA 2014. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2015 · Glia
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