Immune Privilege as an Intrinsic CNS Property: Astrocytes Protect the CNS against T-Cell-Mediated Neuroinflammation

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.