Role of the Gut Microbiota in TH cell differentiation, especially TH 17

TH17 (T helper 17) has emerged as a novel potential therapeutic agent for the control of intestinal inflammatory conditions. These cells are most abundant in the small intestinal lamina propris. IL-17 (Interleukin 17A) expressing CD4+T lymphocytes (Th17) cells naturally reside in the intestine’s lamina propria where specific cytokines and microbiota, such as segmented filamentous bacteria (SFB), promote the differentiation. To control the intestinal inflammatory conditions the strategy would be to block Th 17 cell differentiation and expansion, cytokine neutralization produced by the Th17 cells and inhibition of transcription factor specific to TH17 cells. These studies have been evaluated using the murine model.

 

Blocking the Differentiation and Amplification of Th17 cells

The innate immune cells, like DC (dendritic cells) and macrophages, and their cytokines, such as IL-1β. IL-6,IL-21,and IL-23, play a key role in differentiation and proliferation of TH17 cells; the use of neutralizing monoclonal antibodies for these cytokines or the antagonism of their receptors might be reasonable strategies for the treatment of intestinal disorders.

Fina, et al. [1] said that the blockade of IL-21R by the administration of IL-21R/Fc attenuates inflammation in mice and also said that neutralization of IL-21 by an antibody reduced IL-17 secretion by lamina propria lymphocytes isolated from intestinal inflammatory diseases. Similarly, neutralizing IL-21 antibody to mice with dextran-sodium-sulfate-induced colitis decreased the colonic T-cell infiltrate and the production of IL-6 and Il-17A in the inflamed colonic tissue. Recently the use of monoclonal antibody against ustekinumab and their success in inflammatory diseases might be due to their ability to simultaneously inhibit TH1 and TH17 cells: both of them are clearly implicated in intestinal inflammatory disorders.

Inhibition and/or Neutralization of TH17 cytokines

Zhang, et al. [2] reported that IL-17R knockout mice were significantly protected against colonic inflammation when compared to wild–type mice, and also stated that the over expression of IL-17A IgG1 fusion protein significantly attenuated colonic inflammation after acute trinitrobenzene-sulphonic-acid-induced colitis. As a contrasting result has been obtained in the human studies, such as a human anti-IL17A antibody failing to show any beneficial effect in intestinal inflammatory patients, now the studies are focused on evaluating a combined IL-17A and IL-17F blockade as a potential strategy for intestinal inflammatory therapy. Fitzpatrick, et al. [3] used vidofludimus, a novel oral immunomodulatory drug that inhibits dihyroorotate dehydrogenase and lymphocyte proliferation; the study showed the reduced expression of IL-17A and IL-17F, through the inhibition of STAT3 and nuclear factor-ᶄB activation. While considering the Th17 plasticity, the Th17 cells lose their ability to secrete the IL-17A and turn into IFN-α producers. They express a high level of aryl hydrocarbon receptor (AhR), a transcription factor expressed in the vertebrate cells, which mediates the range of the cellular events in response to different ligands including derivatives of tryptophan, such as 6-formylindolo (3,2-b) carbazole (Ficz). Activation of AhR results in enhanced production of IL-22, together with the reduction of Th1 and Th2 cytokines, as reported by Veldhoen, et al. [4].

Inhibition of TH17 cell specific transcription factors

Veldhoen [5] reported that the pharmacological target was the transcription factors RORӯt and STAT3, which control the TH17 polarization and function. Others proposed that the beneficial effects exerted by mesenchymal stem cells in experimental colitis can be associated with a down regulation of both TH1-TH17 driven autoimmune and inflammatory responses derived from the inhibition of RORӯt activity, together with the activation of CD4(+)CD25(+)Foxp3(+)Treg cells. Recently Fitzpatrick & Ulanovsky [6] described synthetic triterpenoids, dual small molecule inhibitors of NF-ᵏB and STAT3, which may also have potential benefits in intestinal inflammation.

Future perspectives

Although much progress has been made in revealing the role of TH17 cells during intestinal inflammation, there is still lot to be learned. Therefore, a better understanding of this novel agent could lead to development of effective biological agents for intestinal inflammatory diseases.

References

1. Fina D, & Pallone F (2008) What is the role of cytokines and chemokines in IBD? Inflamm Bowel Dis 14 Suppl 2: S117-118.

2. Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK (2006) Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 12: 382-388.

3. Fitzpatrick LR, Small JS, Doblhofer R, Ammendola A (2012) Vidofludimus inhibits colonic interleukin-17 and improves hapten-induced colitis in rats by a unique dual mode of action. J Pharmacol Exp Ther 342: 850-860.

4. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, et al. (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453: 106-109.

5. Veldhoen M (2009) The role of T helper subsets in autoimmunity and allergy. Curr Opin Immunol 21: 606-611.

6. Fitzpatrick D, Ulanovsky N (2014) Editorial overview: neural maps. Curr Opin Neurobiol 24: iv-vi.

Laure Bindels
Laure Bindels
Satheesh Natarajan, Ph.D., is a postdoctoral research fellow at the Laboratory of Biomedicine and Molecular Immunology, University of Veterinary Medicine and Pharmacy, in Kosice, Slovakia. His work is in immunology and molecular biology.