Saturday, 12 January 2013

Research: Killing cells spread the misery

EpubJi et al. MHC class I-restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8(+) T cells. Nat Immunol. 2013 Jan doi: 10.1038/ni.2513.

Myelin presentation to T cells in the central nervous system (CNS) sustains inflammation in multiple sclerosis (MS). CD4(+) and CD8(+) T cells contribute to MS, but only cells that present myelin to CD4(+) T cells have been identified. We show that MHC class I-restricted myelin basic protein (MBP) was presented by oligodendrocytes and cross-presented by Tip-dendritic cells (DCs) during experimental autoimmune encephalomyelitis (EAE), an animal model of MS initiated by CD4(+) T cells. Tip-DCs activated naive and effector CD8(+) T cells ex vivo, and naive MBP-specific CD8(+) T cells were activated in the CNS during CD4(+) T cell-induced EAE. These results demonstrate that CD4(+) T cell-mediated CNS autoimmunity leads to determinant spreading to myelin-specific CD8(+) T cells that can directly recognize oligodendrocytes.

For many years EAEers just focused on CD4 T cells but when pathologists said there were more CD8 T cells (Virus killing cells) in MS. The modellers turned their attention to CD8. When CD8 recognise their target is usually a virus) in the context of self their response is to kill the infected cell. Tip-Dendritic cells are a type of antigen presenting cells (T cell stimulating cell) that make tumour necrosis factor and nitric oxide. In contrast to oligodendrocytes being a target this study suggests that oligodendrocytes present the myelin to T cells. In this study they show that CD8 cells can be stimulated by Tip Dendritic cells which form from infiltrating macrophages.
In the past we talked about MHC class I (press link) and How T cells are stimulated (press link) and in this current study they made an antibody that could detect myelin-loaded MHC class I. They then used that to probe the CNS and found that Tip-DC rather than microglia are expressing this. So the Tip DC are the antigen presenting cell (or target). They show that the DC do not make myelin so they must be scavenging it an presenting it. They call this "cross-presentation" most other peoples vocabulary it is simple antigen presentation, to distinguish it from a peptide made within the cell, which would occur in virally infected cells. So if they start with a CD4-mediated disease through the infiltration of Tip DC and acquisition of myelin peptides (maybe following oligodendrocyte attack because they express MHC class I and myelin) a CD8 response can be started. Furthermore a response to one myelin antigen can this led to a response to another myelin antigen. This is all very interesting.

It is inferred that this activation all occurs in the CNS, largely because CD8 cells in CNS display an effector/activated phenotype (CD44high, CD62Low) compared to the periphery (CD44 low, CD62Lhigh). However in my opinion this would be expected because CD44 is an adhesion molecule that is required to get cells in brain. We showed that if you take a mixed bag of blood cells specific for an irrelevant antigen inject them into the blood during EAE and low what happens 2 hours later the CD44low CD62L cells have got in to lymph glands and the CD44high, CD62Low are in the brain. It has more to do with selective migration than activation.

However, this study does show an example of diversity of autoimmune targets could evolve.

1 comment:

  1. Is this bad news for the EBV hypothesis?


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