Sunday, March 18, 2018 5:39:59 PM
... just for anyone following my discussion with hschlauch (Hi! :o) about IDO or not: actually it's much, much more complex than I thought.
So I was reading "Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation"
(http://www.cell.com/cancer-cell/comments/S1535-6108(18)30058-8), which completes the picture when/why an immune cell shows increased PD-1 receptors on it's surface. Usually this is just triggered by activation ("TCR signaling-induced PD-1 expression is a rapid process with an observed increase at the time point of 5 hr."), but an environment high in Kynurenine happens to trigger another pathway ("Kyn alone was sufficient to upregulate PD-1 in resting CD8+ T cells. However, such induction was a slow process with an initial increase at the time point of 72 hr. ... Thus, CD8+ T cells have early and late PD-1 expression patterns."). In total this paper postulates a path of "IFN-gamma (by CTL) -> IDO1/Ahr (in tumor-repopulating cells) -> Kyn -> PD-L1 (in CD8+)".
So, if one ignores the effect of IDO1 and Kyn in and on any other cell type, this paper supports the inhibition of the IDO1-Kyn-AhR pathway (albeit as something with little incremental value compared to anti-PD-1 or anti-PD-L1).
So I still thought this confirmed IDO1-Kyn-AhR as being the "bad guys" in all respects (which they often are, see e.g. *1 for current science about AhR in TNBC).
Yet, for the original problem of Treg/Teff balance, I am not so certain any longer about the effect of IDO1 inhibition.
I should say I had to read it several times to understand it. However, one of the many IDO1 inhibitors (which actually isn't an IDO1 inhibitor in a true sense), actually activates AhR (see *2). It took me some time, but this seems to be an effect hypothesized by other scientists (see *3).
In short, some specific type of AhR-activation appears to prevent T-cells becoming iTregs and makes them Th17 instead.
Wow. Not all activation downstream IDO1 is bad.
dM
*1
*2
*3
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