For those of you not old enough to remember “Life on Mars”….yes it was a TV programme about a Cop who travelled back in time to the 1970s..sexism, bad haircuts, those platform shoes and hideous clothes and all that stuff ….with flash backs to a TV cop show called the Sweeney (The flying squad), who would go after armed robbers and yes it is a David Bowie song from the 1970s.
So today we are off back in time to the 1970s, to the science that time forgot. Maybe this is the going back in a circle and is it the death of the T reg?.
For regular readers of the Blog this new concept will come as no surprise
Depletion of CD52-positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune-tolerance promoting CD8 T-cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis. von Kutzleben S, Pryce G, Giovannoni G, Baker D. Immunology. 2017;150(4):444-455
However, it may now throw a spanner in the works for the Lemmings
We have come to the stage where it is now recognised that CD8 T cells are the dominant T cells in MS. CD8 T cells are the cytotoxic cells that can kill virally infected cells. Dimethyl fumarate gets rid of them, even CD20 gets rid of them, an AAN abstract would kid you thats how it works, but what happens if we specifically get rid of them, say with a CD8 specific antibody. Surely this is coming.
However for the old farts like me, who were around in the 1970s, we can remember that CD8 cells were called T suppressor/cytotoxic cells. A subset of cells that regulated the immune response. At that time every mouse experiment the disease was controlled by Ly (CD8) suppressor T cells. However, they fell out of favour in the 1980’s when they couldn’t be cloned and so anergy and Th1 & Th2 arrived, before T regulatory cells arrived. Now history is repeating itself, done by someone who was there in the 1970’s
So new technology to an old problem and lets see what T cells react to. I told you this was coming. Surprsingly it is here in mice first, humans next.
Opposing T cell responses in experimental autoimmune encephalomyelitis, Nature (2019). DOI: 10.1038/s41586-019-1467-x , https://nature.com/articles/s41586-019-1467-x
Experimental autoimmune encephalomyelitis is a model for multiple sclerosis. Here we show that induction generates successive waves of clonally expanded CD4+, CD8+ and γδ+ T cells in the blood and central nervous system. We also find major expansions of CD8+ T cells in patients with multiple sclerosis. In autoimmune encephalomyelitis, we find that most expanded CD4+ T cells are specific for the inducing myelin peptide MOG35–55. By contrast, surrogate peptides derived from a yeast peptide major histocompatibility complex library of some of the clonally expanded CD8+ T cells inhibit disease by suppressing the proliferation of MOG-specific CD4+ T cells. These results suggest that the induction of autoreactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells.
In this study they looked for specificity and for the CD4 T cells they found that they reacted to the protein that had been used to induce disease. But for the CD8 cells, no. So now they went on a “fishing trip” and created billions of peptides embedding into the major histocompatibility complex class I which CD8 need to see to be activated that and hunted to see what the CD8 T cells reacted to. They they called this ” crowdsourcing the T cells “. To their surprisie these were regulatory and not pathogenic. The suppressor T cell reappeared, but they have missed a trick and called them regulatory T cells…how confusing.
None of the peptides identified after numerous rounds of screening came from mouse proteins, and the authors call them ‘surrogate’ peptides, to indicate that they probably stand in for self peptides normally present in the body. These cells form about 5% of the CD8 population and express soe identifying markers.
If you read the press surrounding this paper, there was a bit of a reawakening, perhaps that had started the paper idea with what T cells react to is unknown” …..when they realised that these cells were discovered in the 1970s. When you have dementia your old age memories are left intact, so the senior authors of the paper you would think, would not need an epiphany.
Therefore this paper in one of the best science comics, reinvents the wheel and tells us there is a type of regulatory cell that we knew about fifty years ago. Could we harness these to do some good