Differential immune cell dynamics in the CNS cause CD4+ T cell compartmentalization

Abstract

In the course of autoimmune CNS inflammation, inflammatory infiltrates form characteristic perivascular lymphocyte cuffs by mechanisms that are not yet well understood. Here, intravital two-photon imaging of the brain in anesthetized mice, with experimental autoimmune encephalomyelitis, revealed the highly dynamic nature of perivascular immune cells, refuting suggestions that vessel cuffs are the result of limited lymphocyte motility in the CNS. On the contrary, vessel-associated lymphocyte motility is an actively promoted mechanism which can be blocked by CXCR4 antagonism. In vivo interference with CXCR4 in experimental autoimmune encephalomyelitis disrupted dynamic vessel cuffs and resulted in tissue-invasive migration. CXCR4-mediated perivascular lymphocyte movement along CNS vessels was a key feature of CD4(+) T cell subsets in contrast to random motility of CD8(+) T cells, indicating a dominant role of the perivascular area primarily for CD4(+) T cells. Our results visualize dynamic T cell motility in the CNS and demonstrate differential CXCR4-mediated compartmentalization of CD4(+) T-cell motility within the healthy and diseased CNS.

Cytotoxic CD8+T Cell–Neuron Interactions: Perforin-Dependent Electrical Silencing Precedes But Is Not Causally Linked to Neuronal Cell Death

“…In the absence of the cognate antigen, activated CMTMR-labeled WT OT-I T cells rapidly entered acute hippocampal slices and showed a typical random migratory behavior in the densely packed neuronal banners of the CA region as described previously (Donnadieu et al, 1994;Siffrin et al, 2009) (Fig. 8 A).…”

Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors

“…A fraction of migrating cytotoxic CD8 + T cells was found to follow blood vessels during the late phase of tumor rejection in a tumor mouse model (28). Moreover, specific aggregates of CD4 + T cells proximate to blood vessels have been observed in human glioblastoma, as well as in brains of patients or mice with autoimmune inflammation (36,37).…”

The Role of CD8+ T Cells and Their Local Interaction with CD4+ T Cells in Myelin Oligodendrocyte Glycoprotein35–55–Induced Experimental Autoimmune Encephalomyelitis

“…Operation procedures and TPLSM were performed, as previously described by Siffrin et al (24,25). Mice were anesthetized with 1.5% isoflurane in oxygen/nitrous oxide (2:1) using a facemask.…”

“…The anesthetized animal was transferred to a custom-built operation and microscopy table and fixed in a hanging position. The preparation of the imaging field was performed according to adapted protocols for cortical imaging (24). In brief, the brain stem was exposed by carefully removing musculature above the dorsal neck area and removing the dura mater between the first cervical vertebra and occipital skull bone.…”