Regional and functional heterogeneity of antigen presenting cells in the mouse brain and meninges

Abstract

The central nervous system (CNS) is considered to be immune privileged, owing in part to the absence of major histocompatibility (MHC) class II + cells in the healthy brain parenchyma. However, systemic inflammation can activate microglia to express MHC class II, suggesting that systemic inflammation may be sufficient to mature microglia into functional antigen presenting cells (APCs). We examined the effects of systemic lipopolysaccharide (LPS)-induced inflammation on the phenotype and function of putative APCs within the mouse brain parenchyma, as well as its supporting tissues-the choroid plexus and meninges. Microglia isolated from different regions of the brain demonstrated significant heterogeneity in their ability to present antigen to naïve OT-II CD4 + T cells following exposure to systemic LPS. Olfactory bulb microglia (but not cortical microglia) intimately interacted with T cells in vivo and stimulated T cell proliferation in vitro, albeit in the absence of co-stimulation. In contrast, myeloid cells within the choroid plexus and meninges were immunogenic and upregulated the co-stimulatory molecule CD80 following systemic inflammation. Dural APCs, which clustered around LYVE-1 + lymphatics, were more efficient at stimulating naïve T cell proliferation than choroid plexus APCs, suggesting that the dura may be an underappreciated site for immune interactions. This study has highlighted the functional diversity of myeloid cells within the sub-compartments of the CNS and its supporting tissues. Furthermore, these findings demonstrate that systemic inflammation can mature selected microglia populations and choroid plexus/meningeal myeloid cells into functional APCs, which may contribute to the pathogenesis of neuroinflammation and neurodegenerative diseases. K E Y W O R D Santigen presenting cells, brain parenchyma, central nervous system, meninges, microglia

Midbrain microglia mediate a specific immunosuppressive response under inflammatory conditions

“…Accordingly, a higher concentration of CD4 + T lymphocytes was observed in the midbrain suggesting that an interplay between microglia and CD4 + T cells might occur in this region. Microglia with antigen-presenting properties are a rare cell type in the brain parenchyma, although a subpopulation of these cells was identified in the olfactory bulb after LPS stimulation [37]. Regionally heterogeneous gene expression profiles show that the transcriptome of cortical and striatal microglia differs from that of hippocampal microglia in genes involved in the immune response and in antigen presentation [14].…”

“…Using different approaches, we demonstrate that LPS elicits a heterogeneous response in different brain regions. A context-dependent response of microglia to LPS has been described in the cortex and olfactory bulbs, even in the absence of morphological changes [37]. Flow cytometry analysis of thousands of CD45 low CD11b + cells indicated that the fraction of FCS hi /SSC hi microglia increases in all brain regions (from ≈ 5 to ≈ 20%), suggesting that approximately 15% of the cells in the brain parenchyma experienced morphological changes and do not respond homogenously to LPS.…”

Microglia versus Monocytes: Distinct Roles in Degenerative Diseases of the Retina

“…The increase in MNPs numbers is due to microglia proliferation, and monocyte infiltration in certain conditions [5,30]. A subpopulation of Cd11c + MNPs was also described [31,32]. Histological studies of human postmortem retinas suggest that subretinal MNPs are invariably present in intermediate and advanced (or 'late') forms of AMD [6,19,[33][34][35].…”

Meningeal Lymphatics: From Anatomy to Central Nervous System Immune Surveillance

“…Nevertheless, numerous studies have reported that meningeal DCs survey the brain parenchyma and promote or constrain CNS immunity. This occurs through migration to the cervical lymph nodes and reactivation of T cells following their infiltration into the CNS (29)(30)(31)(32)(33)(34)(35). Tissue-resident DCs normally serve as phagocytes, but once activated, they process the Ag and carry it to lymph nodes where they function as potent APCs (36).…”