Treg17 cells

Helper T cells are essential part of body's immune system. These cells are divided in many subsets based upon their ability to produce different cytokines. Following the discovery of interleukin-17 (IL-17) producing T helper (Th17) cells as a distinct lineage of T helper cells it became clear that these cells play an important role in the host defense and participate in the pathogenesis of many inflammatory and autoimmune diseases. The Th17 cells can alter their differentiation program ultimately giving rise to either protective or pro-inflammatory pathogenic cells. The protective and non-pathogenic Th17 cells are termed as Treg17 cells.[1]

Activation

Like conventional regulatory T cells (Treg), induction of regulatory Treg17 cells could play an important role in modulating and preventing certain autoimmune diseases. Treg17 (Regulatory Th17) cells are generated from CD4+ T cells. Treg17 cells with regulatory phenotype with in vivo immune-suppressive properties in the gut have also been identified as rTh17 cells.[2] Similar to Th17 cells the Treg17 development depended on the transcription factor Stat3.[3]

Function

These regulatory Th17 cells are generated by TGF-beta plus IL-6 in vitro. They produce IL-17 and IL-10 and low level of IL-22 and suppress autoimmune and other immune responses. CD4+ T cells polarized with IL-23 and IL-6 are pathogenic upon adoptive transfer in type 1 diabetes while cells polarized with TGF-beta and IL-6 are not pathogenic.,[4][5] The intracellular aryl hydrocarbon receptor (AhR), which is activated by certain aromatic compounds, is specifically expressed in Treg17 cells.[6] These cells are regulated by IL-23 and TGF-beta.[7][8][9] The production of IL-22 in this subset of Th17 cells is regulated by AhR and Treg17 cells are depend on activation of the transcription factor Stat3. In a steady state, TGF-beta and AhR ligands induce low expression of IL-22 along with high expression of AhR, c-MAF, IL-10, and IL-21 that might play a protective role in cell regeneration and host microbiome homeostasis.

Clinical significance

Treg17 cells regulate the function of Th17 cells that are important role in the host defense against fungal and bacterial pathogens and participate in the pathogenesis of multiple inflammatory and autoimmune disorders. Selective deletion of Stat3 caused spontaneous severe colitis because of the lack of Treg17 cells and increase in pathogenic Th17 cells. The mechanism of Treg17 cell action is expression of chemokine receptor CCR6, which facilitates trafficking into areas of Th17 inflammation. This is also seen in human disease such Glomerulonephritis (GN) in kidney. Conversion of pathogenic Th17 cells in vivo at the conclusion of an inflammatory disease process by TGF-β results in the generation of Treg17 like cells.[10] There is also conservation across species of Treg17 cells.

References

  1. ↑ Singh, B; Schwartz, JA; Sandrock, C; Bellemore, SM; Nikoopour, E (2013). "Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells". Indian J Med Res. 138: 591–4. PMC 3928692Freely accessible. PMID 24434314.
  2. ↑ Esplugues, E; 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 (2011). "Control of TH17 cells occurs in the small intestine". Nature. 475: 514–8. doi:10.1038/nature10228. PMID 21765430.
  3. ↑ Chaudhry, A; Rudra, D; Treuting, P; Samstein, RM; Liang, Y; Kas, A; Rudensky, AY (2009). "CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner". Science. 326: 986–91. doi:10.1126/science.1172702. PMID 19797626.
  4. ↑ Bellemore, SM; Nikoopour, E; Schwartz, JA; Krougly, O; Lee-Chan, E; Singh, B (2015). "Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic mice". Clin Exp Immunol. 182 (3): 261–9. doi:10.1111/cei.12691. PMID 26250153.
  5. ↑ Nikoopour, E; Schwartz, JA; Huszarik, K; Sandrock, C; Krougly, O; Lee-Chan, E; Singh, B (2010). "Th17 polarized cells from nonobese diabetic mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes". J Immunol. 184: 4779–88. doi:10.4049/jimmunol.0902822. PMID 20363968.
  6. ↑ Stockinger B, Di Meglio P, Gialitakis M, Duarte JH. 2014. The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol. 32:403-32. doi 10.1146/annurev-immunol-032713-120245. PMID 24655296
  7. ↑ Kluger, MA; Luig, M; Wegscheid, C; Goerke, B; Paust, HJ; Brix, SR; Yan, I; Mittrücker, HW; Hagl, B; Renner, ED; Tiegs, G; Wiech, T; Stahl, RA; Panzer, U; Steinmetz, OM (2014). "Stat3 programs Th17-specific regulatory T cells to control GN.". J Am Soc Nephrol. 25: 1291–302. doi:10.1681/ASN.2013080904. PMID 24511136.
  8. ↑ Ghoreschi, K; Laurence, A; Yang, XP; Tato, CM; McGeachy, MJ; Konkel, JE; et al. (2010). "Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling". Nature. 467: 967–71. doi:10.1038/nature09447. PMC 3108066Freely accessible. PMID 20962846.
  9. ↑ "TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.". Nat Immunol. 8: 1390–7. Dec 2007. doi:10.1038/ni1539. PMID 17994024.
  10. ↑ Gagliani N, Vesely MC, Iseppon A, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature. 2015 Apr 29. doi: 10.1038/nature14452. PMID 25924064
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