Are Microglial Cells the Regulators of Lymphocyte Responses in the CNS? (original) (raw)
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Immunology Today, 2000
mmune privilege of the CNS is thought to be maintained by the tight endothelial junctions of the blood-brain barrier (BBB), the absence of adequate connections with the immune system, and the presence of an immunosuppressive microenvironment. This strict regulation of CNS immune reactivity is overcome in neuroinflammatory disorders, in which large numbers of leukocytes are recruited to the CNS, often leading to irreversible neurological impairment. T cells are thought to play a key role in initiating and perpetuating the disruptive inflammatory process associated with multiple sclerosis (MS), a putative autoimmune disease affecting the CNS white matter, or with certain neurotrophic virus infections 1 . Despite intensive investigation, the events underlying the recognition of CNS-associated antigens by T cells remain poorly defined. One of the most debated and controversial issues is whether, and to what extent, cells residing in the CNS participate in the stimulation and/or the reactivation of CNS-targeted T cells.
Microglia: gatekeepers of central nervous system immunology
Journal of Leukocyte Biology, 2008
Microglia are perhaps the most underestimated cell type of our immune system. Not only were immunologists unaware of their capabilities until recently, but also, some neuroscientists denied their actual existence until the late 20th century. Nowadays, their presence is confirmed extensively, as demonstrated by numerous reports describing their involvement in virtually all neuropathologies. However, despite distinct approaches, their origin remains a point of controversy. Although many agree about their myeloid-monocytic ancestry, the precise progenitor cells and the differentiation mechanisms, which give rise to microglia in the different developmental stages of the CNS, are not unraveled yet. Mostly, this can be attributed to their versatile phenotype. Indeed, microglia show a high morphological plasticity, which is related to their functional state. This review about microglia aims to introduce the reader extensively into their ontogeny, cell biology, and involvement in different neuropathologies. J. Leukoc. Biol. 85: 000 -000; 2009.
Microglia and Microglia-Like Cell Differentiated from DC Inhibit CD4 T Cell Proliferation
PLoS ONE, 2009
The central nervous system (CNS) is generally regarded as a site of immune privilege, whether the antigen presenting cells (APCs) are involved in the immune homeostasis of the CNS is largely unknown. Microglia and DCs are major APCs in physiological and pathological conditions, respectively. In this work, primary microglia and microglia-like cells obtained by co-culturing mature dendritic cells with CNS endothelial cells in vitro were functional evaluated. We found that microglia not only cannot prime CD4 T cells but also inhibit mature DCs (maDCs) initiated CD4 T cells proliferation. More importantly, endothelia from the CNS can differentiate maDCs into microglia-like cells (MLCs), which possess similar phenotype and immune inhibitory function as microglia. Soluble factors including NO lie behind the suppression of CD4 T cell proliferation induced by both microglia and MLCs. All the data indicate that under physiological conditions, microglia play important roles in maintaining immune homeostasis of the CNS, whereas in a pathological situation, the infiltrated DCs can be educated by the local microenvironment and differentiate into MLCs with inhibitory function.
Microglia and central nervous system immunity
Neurosurgery clinics of North America, 2010
The central nervous system (CNS) has evolved as an immune-privileged site to protect its vital functions from damaging immune-mediated inflammation. There must be a CNS-adapted system of surveillance that continuously evaluates local changes in the nervous system and communicates to the peripheral immune system during an injury or a disease. Recent advances leading to a better understanding of the CNS disease processes has placed microglia, the CNS-based resident macrophages, at center stage in this system of active surveillance. Evidence points to microglia cells contributing to the immunosuppressive environment of gliomas and actually promoting tumor growth. Microglia accumulation exists in almost every CNS disease process, including CNS tumors. This article discusses the role of microglia in CNS immunity and highlights key advances made in glioma immunology.
Microglial Activation Milieu Controls Regulatory T Cell Responses
The Journal of Immunology, 2013
Although mechanisms leading to brain-specific inflammation and T cell activation have been widely investigated, regulatory mechanisms of local innate immune cells in the brain are only poorly understood. In this study, to our knowledge we show for the first time that MHC class II + CD40 dim CD86 dim IL-10 + microglia are potent inducers of Ag-specific CD4 + Foxp3 + regulatory T cells (Tregs) in vitro. Microglia differentially regulated MHC class II expression, costimulatory molecules, and IL-10 depending on the amount of IFN-g challenge and Ag dose, promoting either effector T cell or Treg induction. Microglia-induced Tregs were functionally active in vitro by inhibiting Ag-specific proliferation of effector T cells, and in vivo by attenuating experimental autoimmune encephalomyelitis disease course after adoptive transfer. These results indicate that MHC class II + CD40 dim CD86 dim IL-10 + microglia have regulatory properties potentially influencing local immune responses in the CNS.
Journal of Leukocyte Biology
Resting microglia comprise up to 13% of the cells in human central nervous system (CNS) white matter. Their large number and dendritic morphology make them ideally suited to survey the CNS for noxious stimuli. Upon activation microglia gradually lose dendritic processes and transform into typical phagocytic macrophages. Microglia have been implicated as the main antigen presenting cell within the CNS, and appear to be of central importance as effectors and regulators of demyelination. To further characterize the capacity for immune reactivity within the human CNS, we have studied several characteristics of microglia, both in situ and in vitro. We find that human microglia have ultrastructural, phenotypic (CD11c, CD68, acid phosphatase), and functional (FcR and CR mediated phagocytosis) properties typical for cells of the monocyte lineage. Our data indicate that microglia also have properties in common with dendritic antigen-presenting cells. Electron microscopy studies show extended...
Journal of Neuroimmunology, 2010
Antigen presentation, a key mechanism in immune responses, involves two main signals: the first is provided by the engagement of a major histocompatibility complex (MHC), class I or class II, with their TCR receptor in lymphocytes, whereas the second demands the participation of different co-stimulatory molecules, such as CD28, CTLA-4 and their receptors B7.1 and B7.2. Specific T-cell activation and deactivation are achieved through this signalling. The aim of our study is to characterise, in the acute experimental autoimmune encephalomyelitis (EAE) model in Lewis rat, the temporal expression pattern of these molecules as well as the cells responsible for their expression. To accomplish that, MBP-immunised female Lewis rats were daily examined for the presence of clinical symptoms and sacrificed, according to their clinical score, at different phases during EAE. Spinal cords were cut with a cryostat and processed for immunohistochemistry: MHC-class I and MHC-class II, co-stimulatory molecules (B7.1, B7.2, CD28, CTLA-4) and markers of dendritic cells (CD1 for immature cells and fascin for mature cells). Our results show that microglial cells are activated in the inductive phase and, during this phase and peak, they are able to express MHC-class I, MHC-class II and CD1, but not B7.1 and B7.2. This microglial phenotype may induce the apoptosis or anergy of infiltrated CD28+ lymphocytes observed around blood vessels and in the parenchyma. During the recovery phase, microglial cells express high MHC-class I and class II and, those located in the surroundings of blood vessels, displayed the B7.2 co-stimulatory molecule. These cells are competent to interact with CTLA-4+ cells, which indicate an active role of microglial cells in modulating the ending of the immune response by inducing lymphocyte activity inhibition and Treg activation. Once clinical symptomatology disappeared, some foci of activated microglial cells (MHC-class II+/B7.2+) were still present in concomitance with CTLA-4+ cells, suggesting a prolonged involvement of microglia in lymphocyte inhibition and tolerance promotion. In addition to microglia, during the inductive and recovery phases, we also found perivascular ED2+ cells and fascin+ cells which are able to migrate to the parenchyma and may play a role in lymphocytic regulation. Further studies to understand the specific function played by these cells are warranted.
Journal of Neuroinflammation, 2014
Background: Tissue-resident antigen-presenting cells (APC) exert a major influence on the local immune environment. Microglia are resident myeloid cells in the central nervous system (CNS), deriving from early post-embryonic precursors, distinct from adult hematopoietic lineages. Dendritic cells (DC) and macrophages infiltrate the CNS during experimental autoimmune encephalomyelitis (EAE). Microglia are not considered to be as effective APC as DC or macrophages. Methods: In this work we compared the antigen presenting capacity of CD11c + and CD11c − microglia subsets with infiltrating CD11c + APC, which include DC. The microglial subpopulations (CD11c − CD45 dim CD11b + and CD11c + CD45 dim CD11b +) as well as infiltrating CD11c + CD45 high cells were sorted from CNS of C57BL/6 mice with EAE. Sorted cells were characterised by flow cytometry for surface phenotype and by quantitative real-time PCR for cytokine expression. They were co-cultured with primed T cells to measure induction of T cell proliferation and cytokine response. Results: The number of CD11c + microglia cells increased dramatically in EAE. They expressed equivalent levels of major histocompatibility complex and co-stimulatory ligands CD80 and CD86 as those expressed by CD11c + cells infiltrating from blood. CD11c + microglia differed significantly from blood-derived CD11c + cells in their cytokine profile, expressing no detectable IL-6, IL-12 or IL-23, and low levels of IL-1β. By contrast, CD11c − microglia expressed low but detectable levels of all these cytokines. Transforming growth factor β expression was similar in all three populations. Although CNS-resident and blood-derived CD11c + cells showed equivalent ability to induce proliferation of myelin oligodendrocyte glycoprotein-immunised CD4 + T cells, CD11c + microglia induced lower levels of T helper (Th)1 and Th17 cytokines, and did not induce Th2 cytokines. Conclusions: Our findings show distinct subtypes of APC in the inflamed CNS, with a hierarchy of functional competence for induction of CD4 + T cell responses.