Zaguia F, Saikali P, Ludwin S, Newcombe J, Beauseigle D, McCrea E, Duquette P, Prat A, Antel JP, Arbour N. Cytotoxic NKG2C+ CD4 T Cells Target Oligodendrocytes in Multiple Sclerosis. J Immunol. 2013 [Epub ahead of print]
The mechanisms whereby immune cells infiltrating the CNS in multiple sclerosis patients contribute to tissue injury remain to be defined. CD4 T cells are key players of this inflammatory response. Myelin-specific CD4 T cells expressing CD56, a surrogate marker of NK cells, were shown to be cytotoxic to human oligodendrocytes. Our aim was to identify NK-associated molecules expressed by human CD4 T cells that confer this oligodendrocyte-directed cytotoxicity. We observed that myelin-reactive CD4 T cell lines, as well as short-term mitogen (PHA)-activated CD4 T cells, can express NKG2C, the activating receptor interacting with HLA-E, a nonclassical MHC class I molecule. These cells coexpress CD56 and NKG2D, have elevated levels of cytotoxic molecules FasL, granzyme B, and perforin (cell killing molecules) compared with their NKG2C-negative counterparts, and mediate significant in vitro cytotoxicity (cell killing capacity) toward human oligodendrocytes, which upregulated HLA-E upon inflammatory cytokine treatment. A significantly elevated proportion of ex vivo peripheral blood CD4 T cells, but not CD8 T cells or NK cells, from multiple sclerosis patients express NKG2C compared with controls. In addition, immunohistochemical analyses showed that multiple sclerosis brain tissues display HLA-E(+) oligodendrocytes and NKG2C(+) CD4 T cells. Our results implicate a novel mechanism through which infiltrating CD4 T cells contribute to tissue injury in multiple sclerosis.
Twenty years ago CD4 postive T cell were the arch enemy in autoimmunity then the pathologists said they were not that common in lesions and that there were more CD8 T cells, suggesting a virus was the proble.So the animal modellers were busy creating CD8 T cell models and now we have this study turning full circle and showing that there are CD4 cells causing damage. Twenty years ago these were called cytolytic cells. CD4 cells usally are stimulated by MHC class II antigens (http://multiple-sclerosis-research.blogspot.co.uk/2012/05/education-what-is-hla.html),but oligodendrocytes do not express MHC class II antigen. However only a few months ago we saw Th17 destroying nerves. How could this be? This study reports that HLA-E is expressed by oligodendrocytes and is recognised by myelin reactive T cells which also express a natural killer cell marker is another mechanism of nerve damage.