T cells bite the dust

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An interesting presentation from this years MSVirtual2020 was presentation by Dr Beatrice Wasser on ‘GlcNac signalling to reduce T cell pathogenicity in MS’.

Abstract

Background: Both adaptive and innate immune cells infiltrate the CNS during multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE). Pathogenic T cells are known as key drivers of the disease while treatment strategies specifically targeting inflammatory processes directly within the CNS parenchyma behind the blood-brain-barrier are still missing.

Objectives: In this project we aimed to unravel CNS-internal mechanisms to counteract the disease in both the murine and the human system by modulating T cell pathogenicity in the CNS.

Methods: We used intravital 2-photon microscopy to visualize T cells and their interactions with neurons and microglia in the CNS of EAE-diseased animals and in organotypic slice cultures. Using immunohistochemistry and flow cytometry we further analyzed surface molecules on T cells and myeloid cells to gain a deeper understanding of the molecular pathways behind the CNS-response to T cell infiltration. Human T cells isolated from blood and cerebrospinal fluid of MS patients were analyzed ex vivo to allow translation to the human system.

Results: We discovered that detrimental effects of pathogenic Th17 cells can be mediated via a cell-to-cell-interaction-dependent vesicular glutamate release pathway that induces damage in neurons. In a counteractive mechanism, microglia attempted to remove fully viable invaded pathogenic T cells from the CNS tissue during the disease. This T cell engulfment was mediated by expression of activation-dependent lectin and its T cell-binding partner, N-acetyl-D-glucosamine (GlcNAc) and enhancement of GlcNAc signaling in the CNS ameliorated disease outcome. In human subjects, we could show that GlcNAc was highly exposed on T cells in the CNS of MS patients. Of note, this GlcNAc exposure on CNS-infiltrated T cells was significantly increased as compared to peripheral T cells.

Conclusions: Myeloid cells are able to directly react to pathogenic T cell infiltration by engulfing living T cells in a GlcNAc-dependent manner. Increased GlcNAc-exposure on T cells in the human CNS reflects high susceptibility of infiltrated T cells to get eliminated by myeloid cells, suggesting that pharmacological enhancement of T cell engulfment could particularly affect T cells in the target organ of MS.

T cells and B cells may be interlopers into the brain, the resident immune system comprising of microglia, macrophages, dendritic cells and granulocytes, however, are not prepared to live this down. The big question has always been how does this resident population react in such circumstances?

Dr Wasser, using a variety of experimental models beautifully demonstrates that direct myeloid cell and T cell interactions can modulate T cell pathogenicity.

Below is a photograph demonstrating Th17 and myeloid cell (CX3CR1+) interactions on the left and interestingly on the right engulfment of a T cell by a myeloid cell.

Figure: Th17 (orange) and myeloid cell (green) interactions

What is the fate of these engulfed T cells?

Overtime they seem to be degraded in the myeloid cells, removing them from the system. Sometimes they even escape (see below).

Figure: Myeloid cell engulfment process of viable pathogenic T cells

How does this work?

The carbohydrate GlcNac (N-Acetyl-D-Glucosamine) expressed on active T cells may be the way they become targeted.

Treatment of EAE mice (an animal model of MS) with GlcNac intrathecally (i.e. directly into the CNS space) led to a reduction in disease severity (see below). Interestingly, this was observed only in the T cells isolated from the CNS and not the spleen (in the periphery) indicating local targeting of the treatment. The small graph on the far right shows that treatment reduces the absolute T cell numbers following treatment.

Figure: GlcNac treatement in EAR

Dr Wasser then goes onto report that there is also increased expression of GlcNac on T cells in the blood and CSF of MS patients, suggesting that the same may apply in humans. A very interesting new treatment to explore!

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Neuro Doc Gnanapavan

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