It's more by curiosity, but I didn't find a convincing mechanism for explaining the opposite effects of IL10 (inhibiting [1]) versus IL6/IL23/IL21 (potentiating) Th17 differentiation on T cells. All these cytokines signal (mainly) through STAT3 which, once phosphorylated, is known to activate Th17 associated transcription factors, so one should expect that IL10 also increases Th17 differentiation, but it's not the case...
Several hypotheses could be:
- that the receptors for these cytokines differentially activate parallel signaling pathways on T cells (such as p38 Map kinase, other STATs). However, several papers claim that the anti-inflammatory effect of IL10 is through STAT3, but they only quote effects on macrophages, not on T cells ... [2]
- that the receptors phosphorylate different loci in STAT3 (and indeed there are different ones [3]), but I didn't find literature on their role on Th17 differentiation
- that IL10R/signaling is not inhibited by SOCS3 while IL6/23/21 is. One could say then that IL6/23/21 induce SOCS3 that suppresses IL6/23/21 signaling but not IL10 signaling, and that IL10 could further increase the amount of SOCS3 in Th17 for instance. But then, would low IL10 doses promote Th17 differentiation ?
Would you have some papers to suggest on this question ?
Best,
References :
[1] Qu et al. 2012 (Experimental Hematology), Mesenchymal stem cells inhibit Th17 cell differentiation by IL-10 secretion
http://dx.doi.org/10.1016/j.exphem.2012.05.006)
[2] Murray 2006 (Curr Opin Pharmacol) Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response - see references 31-33
http://www.ncbi.nlm.nih.gov/pubmed/16713356
[3] Ng et al. 1997 (JBC) STAT3 Is a Serine Kinase Target in T Lymphocytes
http://www.jbc.org/content/272/39/24542.full
Philippe
First it is important to realize that the pro-Th17 cytokine culture conditions favor Th17 differentiation but also generate "a few" Tregs.
With this in mind the attached editorial in Immunity referring to two Immunity papers listed below will at least partially answer your questions.
Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Chaudhry, A., Samstein, R.M., Treuting, P., Yuqiong, L., Pils, M.C., Heinrich, J.-M., Jack, R.S., Wunderlich, F.T., Bruning, J.C., Muller, W., and Rudensky, Y.Y. (2011). Immunity 34, 566–578.
Th17 cells express interleukin-10 receptor and are controlled by Foxp3⁻ and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Huber, S., Gagliani, N., Esplugues, E., O’Connor, W., Jr., Huber, F.J., Chaudhry, A., Kamanaka, M., Kobayashi, Y., Booth, C.J., Rudensky, A.Y., et al.
(2011). Immunity 34, 554–565.
Dear Eric,
Thank you very much !!!, I didn't think about this aspect,
So I guess among the population of T cells under differentiation, IL10 could have at the same time a 'helping' role for both the Th17 and the iTreg cells in the same culture, with iTreg winning the balance ...
Things are WAY more complicated... There are TH17 cells expressing IL-10, the so called "regulatory TH17"...it comes down on how you define TH17 cells...and of course all lymphocyte subsets are man- and not nature-defined...
Esplugues E1, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, O'Connor W Jr, Rongvaux A, Van Rooijen N, Haberman AM, Iwakura Y, Kuchroo VK, Kolls JK, Bluestone JA, Herold KC, Flavell RA. Control of TH17 cells occurs in the small intestine. Nature. 2011 Jul 17;475(7357):514-8.
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