Immune privilege as an intrinsic CNS property: astrocytes protect the CNS against T-cell-mediated neuroinflammation

Abstract

Astrocytes have many functions in the central nervous system (CNS). They support differentiation and homeostasis of neurons and influence synaptic activity. They are responsible for formation of the blood-brain barrier (BBB) and make up the glia limitans. Here, we review their contribution to neuroimmune interactions and in particular to those induced by the invasion of activated T cells. We discuss the mechanisms by which astrocytes regulate pro- and anti-inflammatory aspects of T-cell responses within the CNS. Depending on the microenvironment, they may become potent antigen-presenting cells for T cells and they may contribute to inflammatory processes. They are also able to abrogate or reprogram T-cell responses by inducing apoptosis or secreting inhibitory mediators. We consider apparently contradictory functions of astrocytes in health and disease, particularly in their interaction with lymphocytes, which may either aggravate or suppress neuroinflammation.

Figure 1

Astrocytes activated in a rat model of Parkinson's disease. Astrocytes (arrows) in the globus pallidus of rats after unilateral striatallesion of dopaminergic neurons by injection of 6-hydroxydopamine (6-OHDA). (a) Contralateral hemisphere; astrocytes have short cellular processes. (b) Ipsilateral hemisphere; astrocytes are in an activated state characterised by long cellular processes and enlarged cell bodies with an intense staining. Staining of glial fibrillary acidic protein (GFAP). For detailed information, see [10].

Figure 2

Astrocytes enforce the immune privilege of the CNS (left) at multiple checkpoints employing various mechanisms (right). Astrocytes in the glia limitans are responsible for the exceptional tightness of endothelial tight junctions by producing soluble factors [18]. Despite the BBB, activated T cells (yellow) are able to enter the brain parenchyma (grey) [65]. (1) At the same time, astrocytes in the glia limitans and in the parenchyma may express FasL while activated T cells may express Fas [63, 72, 73]. The ligation of Fas and FasL induces apoptosis of T cells [71]. (2) As this does not fully eradicate infiltrating T cells, the surviving T cells may be restimulated by activated microglia presenting CNS-specific antigens on MHC-II. In the presence of astrocytes, T cells upregulate CTLA-4 [107] which upon ligation of B7 molecules induces a stop of proliferation and anergy of the T cells. (3) IFN-γ produced by invading T cells stimulates astrocytic IL-27 production which suppresses Th17 cells [120, 121, 141]. (4) During sustained T-cell-mediated inflammation, IFN-γ secreted by T cells activates astrocytes to gain the ability to present antigen on MHC-II and costimulate T cells. While this cognate interaction may exacerbate neuroinflammation, it simultaneously leads to an upregulation of NGF production that counteracts neuroinflammation [142]. Also, astrocytes acting as APCs appear to promote Th2 responses and the formation of regulatory T cells [138]. Astrocytes: orange cells; pink: effects leading to CTLA-4 upregulation; green: effects of NGF; dark red: blood; grey: brain parenchyma.