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When encephalitogenic T cells collaborate with microglia in multiple sclerosis

Nature Reviews Neurology volume 15, pages 704–717 (2019)Cite this article

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Abstract

Immune cells mediate critical inflammatory and neurodegenerative processes in the CNS in individuals with multiple sclerosis (MS). In MS, activated microglia, border-associated macrophages and monocyte-derived macrophages in the CNS can encounter T cells that have infiltrated the brain parenchyma from the circulation. Although microglia and T cells both contribute to normal CNS development and homeostasis, evidence suggests that the meeting of activated microglia and macrophages with encephalitogenic T cells exacerbates their capacity to inflict injury. This crosstalk involves many cell-surface molecules, cytokines and neurotoxic factors. In this Review, we summarize the mechanisms and consequences of T cell–microglia interactions as identified with in vitro experiments and animal models, and discuss the challenges that arise when translating this preclinical knowledge to MS in humans. We also consider therapeutic approaches to MS of which the mechanisms involve prevention or modulation of T cell and microglia responses and their interactions.

Key points

  • Microglia and T cells help to maintain homeostasis in the CNS.

  • Activated microglia and macrophages in the CNS interact with T cells via cell-to-cell contact and cytokine-mediated communication to promote neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS).

  • Monocytes and monocyte-derived cells add heterogeneity to the CNS macrophage population in EAE and MS and could also interact with T cells to regulate disease pathology.

  • Several challenges are involved in translating T cell–microglia interactions identified in vitro or in animal models to MS, so these findings should be considered carefully when generalizing to the human disease.

  • The mechanisms of existing and potential MS therapeutics involve interference with the interactions and functions of T cells and microglia, but the contribution of these effects is difficult to confirm.

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Fig. 1: Microglia in the rodent brain at homeostasis.
Fig. 2: T cells in the rodent brain at homeostasis.
Fig. 3: Microglia and T cell interactions in the CNS parenchyma in experimental autoimmune encephalomyelitis and multiple sclerosis.

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Acknowledgements

The authors’ research is supported by operating grants from the Alberta Innovates Health Solutions CRIO Team program, the MS Society of Canada and the Canadian Institutes of Health Research. Y.D. acknowledges postdoctoral fellowship support from the Alberta MS Collaboration. V.W.Y. has salary support from the Canada Research Chair (Tier 1) program.

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    Yifei Dong & V. Wee Yong

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Both authors conceptualized the manuscript. Y.D. wrote the initial draft. V.W.Y. supervised, reviewed and edited the manuscript. Both authors finalized the manuscript.

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Y.D. declares no competing interests. V.W.Y. has received speaker’s and advisory board honoraria from Biogen, EMD Serono, Novartis, Roche, Sanofi-Genzyme and Teva, and educational grants from Biogen, EMD Serono, Novartis, Roche, Sanofi-Genzyme and Teva.

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Glossary

Diapedesis

The migration of leukocytes across the endothelial wall of the blood vessel into the tissue during inflammation.

Homing receptors

Cell adhesion molecules expressed on T cells that recognize their respective ligands expressed by the target tissues or cells, and which facilitate T cell trafficking.

Zitter strain background

A strain of inbred rats that carry the zitter mutation in the Atrn gene and develop neuropathological features of multiple sclerosis, including neurodegeneration, hypomyelination and microgliosis.

γδ T cells

A small set of T cells with unconventional γδ T cell receptors that can recognize non-MHC-restricted antigens such as microbial metabolites, lipids and markers of cell stress.

Parabiosis

An experimental technique in which the vasculature of two animals are surgically united, often used together with fate mapping mouse models to study the migration of immune cells into different tissues.

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Dong, Y., Yong, V.W. When encephalitogenic T cells collaborate with microglia in multiple sclerosis. Nat Rev Neurol 15, 704–717 (2019). https://doi.org/10.1038/s41582-019-0253-6

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