CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system
ABSTRACT 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 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"
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.Glia 04/2015; 63(4). DOI:10.1002/glia.22771 · 6.03 Impact Factor
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- "More interestingly, they also described a population of cells expressing the DC marker CD209 within the CNS parenchyma in close vicinity to blood vessels. Closer analysis revealed that these cells interdigitated with astroglial endfeet and integrated into the glia limitans, where they were presumably poised for interacting with cells in the perivascular space (Prodinger et al., 2011). Indeed, these cells may play an important role as tissue APCs during neuroinflammation; however, their relatively limited abundance together with data showing that MHCII expression on infiltrating cells is required for EAE (Greter et al., 2005) suggests that other APCs strongly contribute to T cell restimulation. "
ABSTRACT: Evidence from experimental autoimmune encephalomyelitis (EAE) suggests that CNS-infiltrating dendritic cells (DCs) are crucial for restimulation of coinfiltrating T cells. Here we systematically quantified and visualized the distribution and interaction of CNS DCs and T cells during EAE. We report marked periventricular accumulation of DCs and myelin-specific T cells during EAE disease onset prior to accumulation in the spinal cord, indicating that the choroid plexus-CSF axis is a CNS entry portal. Moreover, despite emphasis on spinal cord inflammation in EAE and in correspondence with MS pathology, inflammatory lesions containing interacting DCs and T cells are present in specific brain regions.Journal of Neuroimmunology 09/2014; 277(1-2). DOI:10.1016/j.jneuroim.2014.09.016 · 2.79 Impact Factor
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- "Other studies employing CD11c-eYFP mice have revealed ovoid, bipolar, and dendriform CD11c + DCs extensively distributed in the layer II of the piriform cortex as well as periventricular tissues including the rostral migratory stream, which extends caudally from the subventricular zone to the anterior commisure of the olfactory bulb (Bulloch et al. 2008). More recently, CD11c + DC-like cells have been detected in the parenchyma surrounding the vasculature of healthy mouse brain tissue (Prodinger et al. 2010). These DC-like cells seem to be integrated into the glial wall that delimits the perivascular space from the CNS parenchyma, and thus these cells may be poised for communication with infiltrating immune cells. "
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