The Choroid Plexus Functions as a Niche for T-Cell Stimulation Within the Central Nervous System

Abstract

The choroid plexus (CP) compartment in the ventricles of the brain comprises fenestrated vasculature and, therefore, it is permeable to blood-borne mediators of inflammation. Here, we explored whether T-cell activation in the CP plays a role in regulating central nervous system (CNS) inflammation. We show that CD4 T cells injected into the lateral ventricles adhere to the CP, transmigrate across its epithelium, and undergo antigen-specific activation and proliferation. This process is enhanced following peripheral immune stimulation and significantly impacts the immune signaling induced by the CP. Ex vivo studies demonstrate that T-cell harboring the CP through its apical surface is a chemokine- and adhesion molecule-dependent process. We suggest that, within the CNS, the CP serves an immunological niche, which rapidly responds to peripheral inflammation and, thereby, promotes two-way T-cell trafficking that impact adaptive immunity in the CNS.

Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells

“…2c). Previous research showed that T lymphocytes can infiltrate the mouse CP for re-activation and proliferation [28]. To address this phenomenon in the human CP, we studied the spatial association between CD3+ T cells and MHCII+ APCs in the CP stroma.…”

“…As such, the epithelial cell layer in the CP is a pivotal component of the blood-CSF barrier (BCSFB). The BCSFB allows for a tightly regulated bidirectional immunosurveillance system in which immune cells can traffic through the CP into the CNS, but also vice versa [28]. Thus, the CPs, together with the BBB and the meninges, act as regulatory barriers for immune cells between the periphery and the CNS [4,28].…”

“…Immune cells populate the CP under normal conditions, but a detailed overview of immune cell subsets that reside in the CP is currently lacking. The abundance of MHCII+ cells in the CP [32] suggests that the CP may be involved in CSF monitoring and antigen presentation [28]. Upon stimulation, immune cells located at the CP can secrete cytokines or infiltrate into the CNS [17].…”

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

“…Alzheimer's ↑ Lipofuscin vacuoles [301] ↓ Claudin-5, Claudin-1, Occludin, ZO-1 expression [233] ↓ AQP 1 expression [252] Stromal fibrosis Thickening of blood vessel [249] ↓ Mitochondrial activity ↑ Oxidative stress [246] ↓ Megalin expression [239] Basement membrane thickening [249] ↑ IL-1, IL-6, TNFα secretion MMP-3 expression [233] ↑ LRP1 and PgP expression [240] ↓ CSF production [248] CP epithelial cuboidal shape changed ↓ Nucleus size [233] ↓ TTR expression [244] ↑ Concentration of IgG [235] ↑ IFN-I signaling ↓ IFN-γ signaling [236] CP epithelial cell atrophy [241] Parkinson's ↑ VCAM-1 and ICAM-1expression following increase in IFN-γ production [262] ↑ CCL5, CXCL9, CXCL10, CXCL11 expression upon peripheral immune stimuli [266] ALS Leukocyte trafficking through CP requires IFN-y signaling [272] growth factor (VEGF), eNOS and iNOS, which promote the adhesion of leukocytes to vascular walls [217,218]. It was proposed that CP plays a major role as the invasion route for T-cells into the ischemic brain following a stroke.…”

“…Reboldi et al [265] suggested that the migration of T-17 cells through the CP could be regulated by the chemokine receptor CCR-6. Recently, it was found that the CP upregulates chemokines (CCL5 and CXCL9-11) and cell adhesion molecules involved in T cell migration upon peripheral immune stimuli [266]. Other results showed increased levels of the chemokine CX3CL1 in the CP triggered by extracellular adenosinea key mediator of lymphocyte entry into the CNS [267].…”