STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune

[Bob]

I came across this recently, and thought it might be interesting to some who are interested in immunology and immune cells... It's technically way-beyond me, but I'm slowly learning about immune cells etc.

The research is specifically in relation to MS, but seems that it might be relevant to other conditions...

The full paper is available for those who want to get stuck into the detail...

STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation
Wanqiang Sheng, Fan Yang, Yi Zhou, Henry Yang, Pey Yng Low, David Michael Kemeny, Patrick Tan, Akira Moh, Mark H Kaplan, Yongliang Zhang and Xin-Yuan Fu.
Cell Research (2014) 24:1387–1402. doi:10.1038/cr.2014.154; published online 21 November 2014
http://www.nature.com/cr/journal/v24/n12/full/cr2014154a.html

Abstract
T helper (TH)-cell subsets, such as TH1 and TH17, mediate inflammation in both peripheral tissues and central nervous system. Here we show that STAT5 is required for T helper-cell pathogenicity in autoimmune neuroinflammation but not in experimental colitis. Although STAT5 promotes regulatory T cell generation and immune suppression, loss of STAT5 in CD4+ T cells resulted in diminished development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Our results showed that loss of encephalitogenic activity of STAT5-deficient autoreactive CD4+ T cells was independent of IFN-γ or interleukin 17 (IL-17) production, but was due to the impaired expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), a crucial mediator of T-cell pathogenicity. We further showed that IL-7-activated STAT5 promotes the generation of GM-CSF-producing CD4+ T cells, which were preferentially able to induce more severe EAE than TH17 or TH1 cells. Consistent with GM-CSF-producing cells being a distinct subset of TH cells, the differentiation program of these cells was distinct from that of TH17 or TH1 cells. We further found that IL-3 was secreted in a similar pattern as GM-CSF in this subset of TH cells. In conclusion, the IL-7-STAT5 axis promotes the generation of GM-CSF/IL-3-producing TH cells. These cells display a distinct transcriptional profile and may represent a novel subset of T helper cells which we designate as TH-GM.

 

[Bob]

Also, there's an article about the research, here...

New Insights Into “T Helper Cells” Could Guide Future Multiple Sclerosis Therapies
December 1, 2014
by Patricia Inacio, PhD
Multiple Sclerosis News Today
http://multiplesclerosisnewstoday.c...ld-guide-future-multiple-sclerosis-therapies/

It starts...

A recent study entitled “STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation” describes a new subset of T helper immune cells – TH-GM – that express a particular cytokine profile with implications in therapeutics for multiple sclerosis. The study was published in the journalCellResearch.

 

[Bob]

And this is an entirely separate paper, published earlier this year, but it seems to be closely related...

IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells.
Noster R, Riedel R, Mashreghi MF, Radbruch H, Harms L, Haftmann C, Chang HD, Radbruch A, Zielinski CE.
Sci Transl Med. 2014 Jun 18;6(241):241ra80. doi: 10.1126/scitranslmed.3008706.
http://www.ncbi.nlm.nih.gov/pubmed/24944195
http://stm.sciencemag.org/content/6/241/241ra80.short

Abstract
Although T helper 17 (TH17) cells have been acknowledged as crucial mediators of autoimmune tissue damage, the effector cytokines responsible for their pathogenicity still remain poorly defined, particularly in humans. In mouse models of autoimmunity, the pathogenicity of TH17 cells has recently been associated with their production of granulocyte-macrophage colony-stimulating factor (GM-CSF). We analyzed the regulation of GM-CSF expression by human TH cell subsets. Surprisingly, the induction of GM-CSF expression by human TH cells is constrained by the interleukin-23 (IL-23)/ROR-γt/TH17 cell axis but promoted by the IL-12/T-bet/TH1 cell axis. IL-2-mediated signal transducer and activator of transcription 5 (STAT5) signaling induced GM-CSF expression in naïve and memory TH cells, whereas STAT3 signaling blocked it. The opposite effect was observed for IL-17 expression. Ex vivo, GM-CSF(+) TH cells that coexpress interferon-γ and T-bet could be distinguished by differential chemokine receptor expression from a previously uncharacterized subset of GM-CSF-only-producing TH cells that did not express TH1, TH2, and TH17 signature cytokines or master transcription factors. Our findings demonstrate distinct and counterregulatory pathways for the generation of IL-17- and GM-CSF-producing cells and also suggest a pathogenic role for GM-CSF(+) T cells in the inflamed brain of multiple sclerosis (MS) patients. This provides not only a scientific rationale for depleting T cell-derived GM-CSF in MS patients but also multiple new molecular checkpoints for therapeutic GM-CSF suppression, which, unlike in mice, do not associate with the TH17 but instead with the TH1 axis.

 

[Jonathan Edwards]

Thanks for the flag up, Bob,
My view is only my view, as you will have gathered, but I have the usual issues with this. The paper is not about MS but about EAE which is a disease caused in mice specially bred to respond to a whacking dose of self antigen plus adjuvant and then given said whacking dose. MS is not caused like that and we have precious little evidence that it shares much in the way of pathways except at the damage stage. I am not that squeamish but I stopped doing this sort of thing to rodents after the first year of my doctoral project - because I had to do it myself and see the effects.

The second paper is fascinating and Andreas Radbruch, who is good value, is a senior author. The main message seems to be that in humans things are surprisingly different (surprise or maybe not surprise). At least this is about human immunology but I cannot quite see how they link it to MS - unless of course they assume MS is human EAE.

I may be bonkers but I did manage to get the most widely effective therapeutic agent in autoimmunity licensed despite being told by the T cell people that I was wasting my time. There must be some method in my madness? I think all this T cell stuff is off target but I admit to having been a teeny bit wrong before at times - and am happy to be proved wrong again if it helps.

My guess would have been that TH17 would be relevant to the real T cell diseases (not autoimmune) like psoriasis and ankylosing spondylitis. I had a look on Wikipedia and it looks as if IL-17 is looking quite good as a psoriasis treatment but nothing else so far. So not wrong just yet.