Glia-T cell dialogue

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Abstract

Interactions of CD4+ T helper (Th) cells with microglia and astrocytes are likely to play an important role in regulating immune responses as well as tissue damage and repair during infectious and autoimmune central nervous system (CNS) diseases. T cells secreting Th1-type cytokines provide inducing signals for microglia to mature into functional antigen presenting cells (APC). The ability of microglia to act as efficient APC for the restimulation of Th1 cells suggests a role for these cells in the local amplification of pro-inflammatory immune responses. Conversely, the Th2-inducing capacity of microglia and astrocytes together with their ability to produce anti-inflammatory mediators could play a role in providing counter-regulatory signals limiting CNS inflammation. In this article, we review recent studies addressing the functional significance of T cell–CNS glia interactions and present new data on the expression of cyclooxygenase-2, the inducible enzyme involved in prostanoid biosynthesis, in microglia and astrocytes during the course of experimental allergic encephalomyelitis.

Introduction

Following infection by neurotropic pathogens and in autoimmune diseases of the central nervous system (CNS), CD4+ T helper (Th) cells are recruited to the CNS where they are restimulated by the target antigen expressed on local antigen-presenting cells (APC) (Hickey and Kimura, 1988, Pope et al., 1998). CD4+ Th1 cells producing interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-β (TNF-β) promote inflammation, macrophage activation and tissue destruction (Abbas et al., 1996, Mosmann and Sad, 1996). Th1 cells have been implicated in the elimination of neurotropic viruses, in virus-induced CNS immunopathology and in the pathogenesis of CNS autoimmune diseases, such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) (Ando et al., 1989, Finke et al., 1995, Hafler and Weiner, 1995, Issazadeh et al., 1995, Pope et al., 1996). Activation of T cells secreting Th2-type cytokines (IL-4, IL-10, IL-13) with anti-inflammatory activity also occurs during CNS infection and autoimmunity (Kennedy et al., 1992, Woodroofe and Cuzner, 1993, Issazadeh et al., 1995, Morris et al., 1997, Parra et al., 1997) and may play a role in downregulating Th1 responses and macrophage activation (Abbas et al., 1996, Mosmann and Sad, 1996).

Once peripherally primed CD4+ T cells have crossed the blood–brain barrier endothelium and invaded the CNS, their degree of activation and polarization is likely to be influenced by the CNS microenvironment. The synthesis of molecules with immunosuppressive activity like transforming growth factor-β (TGF-β), neuropeptides and gangliosides (Cserr and Knopf, 1992, Irani et al., 1997), the absence or low expression of MHC and adhesion/costimulatory molecules on CNS APC and the apoptotic elimination of T cells (Bauer et al., 1995) have all been proposed as important mechanisms for limiting and/or terminating cell-mediated immune responses within the CNS.

Microglia and astrocytes represent two highly reactive intraparenchymal CNS cell populations which respond to infectious and inflammatory stimuli by upregulating various molecules implicated in the control of immune reactivity (Eddleston and Mucke, 1993, Gehrmann et al., 1995). Microglia can mature into macrophage-like cells capable of secreting pro-inflammatory (IL-1, TNF-α) and anti-inflammatory IL-10, TGF-β, prostaglandin E2 (PGE2) mediators as well as chemokines involved in leukocyte recruitment (Merrill and Benveniste, 1996, Ransohoff, 1997, Minghetti and Levi, 1998). Upregulation of MHC class II and adhesion/costimulatory molecules (CD11a, CD40, CD54, CD80 and CD86) on microglia activated in the course of immune-mediated CNS diseases suggests that this cell type may acquire APC function and play a role in T cell restimulation (De Simone et al., 1995, Gehrmann et al., 1995, Gerritse et al., 1996, Kreutzberg, 1996). Conversely, reactive astrocytes rarely express MHC class II molecules in the inflamed CNS (Kreutzberg, 1996) but produce several mediators that can regulate immune cell function (e.g., PGE2, TGF-β) and recruitment (e.g., the chemokines MCP-1, IP-10 and RANTES) (Merrill and Benveniste, 1996, Ransohoff, 1997, Simpson et al., 1998). In this brief review, we present recent work from our and other laboratories as well as new data indicating that a complex network of interactions between microglia, astrocytes and invading T cells may be involved in determining the balance between Th1- and Th2-regulating signals. This, in turn, may determine the outcome of immune responses within the CNS.

Section snippets

Interactions between microglia and preactivated T cells are important for microglia activation and T cell restimulation

In the normal CNS, microglia display no phagocytic or endocytic activity and express low levels of activation markers (e.g., CD45, CD14, Fc receptors) and MHC class II molecules (Ford et al., 1996, Kreutzberg, 1996). Signals derived from preactivated CD4+ T cells are thought to be crucial for microglia activation. IFN-γ, a cytokine secreted by NK and Th1 cells, induces expression of MHC class II molecules on microglia in vivo and in vitro (Vass and Lassmann, 1990, Shrikant and Benveniste, 1996

Immunoregulatory mediators released by microglia and astrocytes during antigen-specific interaction with T helper cells

Among the factors currently known to influence T helper cell development, cytokines produced by cells of the innate immune system are most important. The production of IL-12 by dendritic cells and monocytes is crucial for Th1 differentiation (Gately et al., 1998). Intracerebral IL-12 synthesis is induced early following viral infection and is thought to play an important role in establishing IFN-γ-dependent resistance and polarization of Th1 responses (Komatsu et al., 1997, Sato et al., 1997).

Microglia and astrocytes express cyclooxygenase-2 during EAE

In more recent experiments, we have asked whether microglia and astrocytes might be induced to express cyclooxygenase-2 (COX-2), the inducible enzyme responsible for the production of high levels of prostanoids, like prostaglandins and thromboxanes, in inflammatory conditions (Mitchell et al., 1995, Minghetti and Levi, 1998). Due to the above-mentioned studies indicating a role for Th1 cells in inducing microglia PGE2 production, we have examined the pattern of expression and cellular

Microglia are more efficient than astrocytes in Th1 restimulation

Recent studies have shown that microglia can act as very efficient APC for the restimulation of Th1 cells. Using Th1 cell lines from OVA TCR transgenic DO11.10 mice and microglia isolated from neonatal mouse brain cultures, we have demonstrated that, in the presence of native OVA or OVA peptide 323–339, IFN-γ-activated microglia stimulate secretion of IL-2, IFN-γ and TNF-α from Th1 cells as well as Th1 proliferation (Aloisi et al., 1998). In a hierarchy of APC, IFN-γ-activated microglia appear

Microglia and astrocytes efficiently restimulate Th2 responses

Th2-type cytokines produced in the CNS during immune-mediated inflammation could play a role in limiting the spreading of Th1 responses (Abbas et al., 1996). Consistent with the anti-inflammatory role of Th2 cytokines, delivery of IL-4 or IL-10 into the CNS inhibits EAE (Mathisen et al., 1997, Croxford et al., 1998, Furlan et al., 1998). We have shown that both microglia and astrocytes can act as powerful APC for the restimulation of Th2 cells (Aloisi et al., 1998). IFN-γ-activated astrocytes

Concluding remarks

A number of Th1- and Th2-regulating factors are produced by reactive microglia and astrocytes in neuroinflammatory pathologies. It is likely that their balance at different stages of the disease process regulates the propagation and destructive consequences of cell-mediated immune responses. Reactivation of Th1 cells by microglia may be relevant for the onset and severity of pro-inflammatory immune responses during infectious and autoimmune CNS diseases. Conversely, the Th2-restimulating

Acknowledgements

This research was supported by the Project on Multiple Sclerosis of the Istituto Superiore di Sanità/Italian Ministry of Health.

References (66)

  • J.E. Merrill et al.

    Cytokines in inflammatory brain lesions: helpful and harmful

    Trends Neurosci.

    (1996)
  • L. Minghetti et al.

    Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide

    Progr. Neurobiol.

    (1998)
  • J.A. Mitchell et al.

    Cyclooxygenase-2: regulation and relevance in inflammation

    Biochem. Pharmacol.

    (1995)
  • M.M. Morris et al.

    Characterization of the cellular and cytokine response in the central nervous system following Semliky Forest virus infection

    J. Neuroimmunol.

    (1997)
  • T.R. Mosmann et al.

    The expanding universe of T-cell subsets: Th1, Th2 and more

    Immunol. Today

    (1996)
  • B. Parra et al.

    Kinetics of cytokine mRNA expression in the central nervous system following lethal and nonlethal coronavirus-induced acute encephalomyelitis

    Virology

    (1997)
  • A.T. Reder et al.

    Prostaglandins and inhibitors of arachidonate metabolism suppress experimental allergic encephalomyelitis

    J. Neuroimmunol.

    (1994)
  • S. Sato et al.

    Central nervous system cytokine mRNA expression following Theiler’s murine encephalomyelitis virus infection

    J. Neuroimmunol.

    (1997)
  • J.E. Simpson et al.

    Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions

    J. Neuroimmunol.

    (1998)
  • M.N. Woodroofe et al.

    Cytokine mRNA expression in inflammatory multiple sclerosis lesions: detection by non-radioactive in situ hybridization

    Cytokine

    (1993)
  • A.K. Abbas et al.

    Functional diversity of helper T lymphocytes

    Nature

    (1996)
  • F. Aloisi et al.

    IL-12 production by central nervous system microglia is inhibited by astrocytes

    J. Immunol.

    (1997)
  • F. Aloisi et al.

    Microglia are more efficient than astrocytes in antigen processing and in Th1 but not Th2 cell activation

    J. Immunol.

    (1998)
  • F. Aloisi et al.

    Opposite effects of interferon-γ and prostaglandin E2 on tumor necrosis factor and interleukin-10 production in microglia: a regulatory loop controlling microglia pro- and anti-inflammatory activities

    J. Neurosci. Res.

    (1999)
  • F. Aloisi et al.

    CD40-CD154 interaction and IFN-γ are required for IL-12 but not prostaglandin E2 secretion by microglia during antigen presentation to Th1 cells

    J. Immunol.

    (1999)
  • F. Aloisi et al.

    Relative efficiency of microglia, astrocytes, dendritic cells and B cells in naive CD4+ T cell priming and Th1/Th2 restimulation

    Eur. J. Immunol.

    (1999)
  • F. Aloisi et al.

    Functional maturation of adult mouse microglia into an antigen presenting cell is promoted by GM-CSF and interaction with Th1 cells

    J. Immunol.

    (2000)
  • B. Becher et al.

    Soluble tumor necrosis factor inhibits interleukin 12 production by stimulated human adult microglial cells in vitro

    J. Clin. Invest.

    (1996)
  • M. Betz et al.

    Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines

    J. Immunol.

    (1991)
  • C.C. Chao et al.

    Neuroprotective role of IL-4 against activated microglia

    J. Immunol.

    (1993)
  • J.L. Croxford et al.

    Cytokine gene therapy in experimental allergic encephalomyelitis by injection of plasmid DNA-cationic liposome complex into the central nervous system

    J. Immunol.

    (1998)
  • R. De Simone et al.

    The costimulatory molecule B7 is expressed on human microglia in culture and in multiple sclerosis acute lesions

    J. Neuropathol. Exp. Neurol.

    (1995)
  • F. Di Rosa et al.

    Lack of Th2 cytokine increase during spontaneous remission of experimental allergic encephalomyelitis

    Eur J. Immunol.

    (1998)
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