MHC Class I Expression and CD8 T Cell Function: Towards the Cell Biology of T-APC Interactions in the Infected Brain
Antigen presentation by major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules is a prerequisite for T cell engagement during the activation as well as the effector phase. The central nervous system (CNS) is unique in that cells resident in the parenchyma, glia and neurons, do not constitutively (or very sparsely at best) express MHC molecules (Aloisi et al., 2000; Sedgwick and Hickey, 1997; Xiao and Link, 1998), making them invisible to T cells. Additional restrictions on T cell surveillance are imposed by the absence of classical lymphatic drainage, the blood—brain barrier (BBB), and the unique anatomy of the brain microvasculature (Bechmann et al., 2007; Galea et al., 2007; Hickey, 2001; Xiao and Link, 1998; Lowenstein, 2002). Infiltrating cells not only have to cross the vascular wall to penetrate into the perivascular space, but more importantly overcome the barrier formed by the glia limitans to access the CNS parenchyma. While the first step is generally not associated with pathology, penetration from the perivascular space of postcapillary venules into the parenchyma is more restricted and once overcome, associated with clinical consequences (Bechmann et al., 2007). In the resting state, perivascular macrophages are maintained by replacement with circulating monocytes. However the glial limitans is not breached, and thus, these cells are considered to be located outside the confines of the BBB. While diffusion of soluble factors and antibodies is restricted by the BBB, especially by the tight, continuous, unfenestrated capillary epithelium, leukocyte infiltration preferentially occurs at distal sites in postcapillary venules (Bechmann et al., 2007). BBB permeability and leukocyte infiltration are thus not necessarily functionally nor physically linked. The barriers separating CNS parenchyma from the circulation explains the rare presence of T cells in the normal CNS parenchyma, despite the ability of peripherally activated and memory T cells to traffic to non lymphoid tissues independent of antigen presentation (Masopust et al., 2004). Nevertheless, T cells activated during an infection or auto-immune response, are able to enter into, and migrate within the brain parenchyma, even in the presence of an intact, non-inflamed BBB (Cabarrocas et al., 2003; Chen et al., 2005; Evans et al., 1996; Hickey, 2001). However, although entry of activated T cells into the CNS is independent of their antigen specificity, only those T cells that recognize antigen are retained. Thus, barriers limiting T cell surveillance of the brain are rapidly overcome following CNS infections and other inflammatory conditions (Griffin, 2003; Ransohoff et al., 2003). Under such conditions, it is also likely that a number of non-activated, bystander T cells, as well as other leukocytes, including B cells are able to penetrate into the brain parenchyma. Mechanisms propagating protective versus pathogenic potential of T cells in varying disease models are complex and require more in depth exploration. This chapter highlights recent advances relating to antigen presentation functions by resident CNS cells and effects exerted by CD8 T cells in vivo with an emphasis on anti-viral functions.
KeywordsWest Nile Virus Central Nervous System Infection Immunological Synapse Central Nervous System Cell Mouse Hepatitis Virus
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