Brain dendritic cells: biology and pathology

Abstract

Dendritic cells (DC) are the professional antigen-presenting cells of the immune system. In their quiescent and mature form, the presentation of self-antigens by DC leads to tolerance; whereas, antigen presentation by mature DC, after stimulation by pathogen-associated molecular patterns, leads to the onset of antigen-specific immunity. DC have been found in many of the major organs in mammals (e.g. skin, heart, lungs, intestines and spleen); while the brain has long been considered devoid of DC in the absence of neuroinflammation. Consequently, microglia, the resident immune cell of the brain, have been charged with many functional attributes commonly ascribed to DC. Recent evidence has challenged the notion that DC are either absent or minimal players in brain immune surveillance. This review will discuss the recent literature examining DC involvement within both the young and aged steady-state brain. We will also examine DC contributions during various forms of neuroinflammation resulting from neurodegenerative autoimmune disease, injury, and CNS infections. This review also touches upon DC trafficking between the central nervous system and peripheral immune compartments during viral infections, the new molecular technologies that could be employed to enhance our current understanding of brain DC ontogeny, and some potential therapeutic uses of DC within the CNS.

Fig. 1

Putative DC within the brain can interact with CD4⁺ T lymphocytes following viral-induced neuroinflammation. Representative confocal Z-stack analysis of a VSV intranasally infected olfactory bulb at 4 (left) and 7 (right) days post-infection. CD11c/EYFP⁺ cells (green) are found throughout glomerular tissue richly populated with CD4⁺ T cells (red). Inset depicts a confocal section in which CD11c/EYFP⁺ cells are in physical contact with CD4⁺ T cells. Representative images from three experiments with an n =3; scale bar 50 μm (10 μm inset)

Fig. 2

Schematic representation of tissue reservoirs believed to be the source of DC infiltration during neuroinflammation. In the steady-state brain Flt3⁺ DC are primarily found within the meninges and choroid plexus. Evidence for DC-like cells has also been found within circumventricular organs such as the area postrema, subfornical organ, median eminence, and pituitary (not depicted for simplicity). During neuroinflammation (e.g., of viral etiology) the DC found within these area are postulated to enter the brain parenchyma in response to cytokine/chemokine gradients. Other potential sources of infiltrating DC are the nasal mucosa, nasal-associated lymphoid tissue, and the blood, in the form of monocyte-derived DC (moDC). Therefore, in light of these various reservoirs, the methods of DC infiltration are believed to range from direct migration into brain tissue, diapedesis followed by crossing of the glia limitans from the Virchow–Robin spaces, and passage from CSF through the CVOs into the brain parenchyma; image not to scale