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  • Review Article
  • Published:

Autoimmune T cell responses in the central nervous system

Nature Reviews Immunology volume 9, pages 393–407 (2009)Cite this article

Key Points

  • Multiple sclerosis is thought to be mediated by autoimmune T cell responses directed against antigens derived from the central nervous system (CNS). The clinical course, symptoms and pathology seen in patients with multiple sclerosis is heterogeneous, suggesting that multiple sclerosis in different patients may result from distinct pathogenic pathways.

  • Autoimmune disease in the CNS occurs when self-reactive T cells specific for CNS antigens are activated in the periphery, either by presentation of the self antigen in the CNS-draining (cervical) lymph nodes or by a molecular mimic of the self antigen. Unlike naive T cells, activated T cells can cross the blood–cerebrospinal fluid (CSF) or blood–brain barrier. Activated T cells are believed to initially cross the blood–CSF barrier and enter the subarachnoid space, where their reactivation facilitates activation of the vascular endothelium and subsequent T cell entry into the perivascular space.

  • The myelin-specific CD4+ T cells that mediate CNS autoimmunity in animal models are usually T cells that circulate in the periphery because they escaped central tolerance owing to low avidity for their cognate antigen.

  • Both CD4+ T helper 1 (TH1) cells, characterized by interferon-γ (IFNγ) secretion, and TH17 cells, characterized by interleukin-17 (IL-17) secretion, can induce CNS autoimmune disease. The interplay between these T cell subsets as well as their interaction with other cells that reside within the CNS is poorly understood but is likely to have an important role in shaping the inflammatory response in different locations within the CNS.

  • During inflammation there are many cell types that can present antigen to CD4+ T cells; the relative contribution and activation state of these different antigen-presenting cells strongly influences the effector function and survival of T cells in the CNS.

  • CD8+ T cells exhibit more evidence of antigen-driven expansion in the CNS of patients with multiple sclerosis, and myelin-specific CD8+ T cells are highly pathogenic in experimental autoimmune encephalomyelitis. However, in addition to CD4+ regulatory T cells, several different types of regulatory CD8+ T cells have been described that may be important in the pathology of multiple sclerosis.

  • Despite the fact that T cells are believed to be the primary effector cells in the pathology of multiple sclerosis, depletion of B cells is a promising therapeutic treatment for patients with multiple sclerosis. It is not yet clear whether the beneficial effect of this therapy is due to disruption of the antigen-presenting function of B cells or their ability to produce antibodies.

Abstract

Autoreactive T cell responses have a crucial role in central nervous system (CNS) diseases such as multiple sclerosis. Recent data indicate that CNS autoimmunity can be mediated by two distinct lineages of CD4+ T cells that are defined by the production of either interferon-γ or interleukin-17. The activity of these CD4+ T cell subsets within the CNS influences the pathology and clinical course of disease. New animal models show that myelin-specific CD8+ T cells can also mediate CNS autoimmunity. This Review focuses on recent progress in delineating the pathogenic mechanisms, regulation and interplay between these different T cell subsets in CNS autoimmunity.

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Figure 1: Anatomical organization of the brain showing the possible routes of activated T cell entry.
Figure 2: Peripheral and CNS activation of myelin-specific CD4+ T cells.
Figure 3: Model of TH1 and TH17 cell differentiation.
Figure 4: Peripheral and CNS activation of myelin-specific CD8+ T cells.

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Acknowledgements

J. Goverman's research is supported by grants from the National Multiple Sclerosis Society (RG3851-A-5) and from the National Institutes of Health (AI073726, AI072737)

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    Joan Goverman

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Glossary

Multiple sclerosis

An inflammatory neurodegenerative disorder characterized by demyelination of bundles of nerves in the central nervous system. Symptoms depend on the site of the lesion but can include sensory loss, weakness in leg muscles, speech difficulties, loss of coordination and dizziness. Multiple sclerosis is thought to be an autoimmune response against components of myelin.

Neuromyelitis optica

A relapsing, demyelinating inflammatory disorder that affects predominantly the optic nerves and spinal cord. Pathogenesis of neuromyelitis optica seems to depend on the generation of antibodies that are specific for aquaporin 4, an abundant water channel in the central nervous system.

Acute disseminated encephalomyelitis

A monophasic, inflammatory, demyelinating disease of the central nervous system, frequently affecting children.

Blood–brain barrier

A physiological barrier between blood vessels and brain parenchyma. It is formed by specialized, tight junctions between endothelial cells of the blood vessel wall, which is surrounded by a basement membrane, and an additional membrane formed from astrocyte feet and microglial cells.

Demyelination

Damage to the myelin sheath surrounding nerves in the central nervous system, which affects the function of the nerves involved.

Tight junction

An intercellular junction that joins the plasma membranes of adjacent epithelial or endothelial cells that regulate paracellular flux. Tight junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.

Oligodendrocyte

The myelin-forming cell of the central nervous system.

Mimicry

Structural similarity between epitopes contained within microbial and host proteins, leading to crossreactivity of T cells in the host.

Wallerian degeneration

The degeneration of an axon distal to a site of injury, which begins to occur about 1.5 days after a lesion is formed.

Degenerate TCR

A T cell receptor (TCR) that can bind to multiple distinct peptide–MHC complexes.

Meninges

The membraneous region surrounding the brain and spinal cord. There are three membranes contained within the meninges: the dura mater (outer), the arachnoid membrane (middle) and the pia mater (inner). The subarachnoid space lies between the arachnoid and pial membranes and is the region in which cerebrospinal fluid flows.

Epitope spreading

This term is used to describe how an immune response generated against a single peptide (or epitope) could spread to include T cell specificities for other peptides (or epitopes) not only on the same autoantigen (intramolecular spreading) but also on other self molecules that are released during the inflammatory response in the target organ.

Plasmacytoid DC

A dendritic cell (DC) that lacks myeloid markers such as CD11c and CD33 but expresses high levels of HLA-DR and CD123. These cells produce high levels of type I interferons (IFNα and IFNβ) after activation.

Perforin

A component of cytolytic granules that participates in the permeabilization of plasma membranes, allowing granzymes and other cytotoxic components to enter target cells.

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Goverman, J. Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9, 393–407 (2009). https://doi.org/10.1038/nri2550

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