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Protein & Cell

, Volume 2, Issue 10, pp 778–781 | Cite as

Romance of the three kingdoms: RORgammat allies with HIF1alpha against FoxP3 in regulating T cell metabolism and differentiation

  • Andy Tsun
  • Zuojia Chen
  • Bin Li
Perspective

Abstract

Regulatory T (Treg) cells play an essential role in immune homeostasis by controlling the function of various immune effector cells, including RAR-related orphan receptor gammat+ (RORγt+) T helper 17 (Th17) cells. Foekhead box P3 (FoxP3) is the master regulator of Treg cell function, while RORγt is the key transcription factor for the induction of the interleukin (IL)-17 family of cytokines during Th17 cell differentiation. FoxP3 can directly interact with and negatively regulate the function of RORγt, to determine the balance between induced Treg (iTreg) and Th17 cell polarization. Two recent independent studies from the Pan and Chi Labs have shown how hypoxia-inducible factor 1 alpha (HIF1α) is able to tip the balance of T cell differentiation toward the Th17 lineage by responding to the local changes in metabolic shift or an increase in proinflammatory mediators in the microenvironment. By allying with HIF1α, RORγt wins the fight against FoxP3 and Treg cell commitment.

Keywords

Rapamycin Th17 Cell Treg Cell Th17 Cell Differentiation Teff Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. An, W.G., Kanekal, M., Simon, M.C., Maltepe, E., Blagosklonny, M.V., and Neckers, L.M. (1998). Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392, 405–408.CrossRefPubMedGoogle Scholar
  2. Battaglia, M., Stabilini, A., Migliavacca, B., Horejs-Hoeck, J., Kaupper, T., and Roncarolo, M.G. (2006). Rapamycin promotes expansion of functional CD4 + CD25 + FOXP3 + regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 177, 8338–8347.CrossRefPubMedGoogle Scholar
  3. Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L., and Kuchroo, V.K. (2006). Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238.CrossRefPubMedGoogle Scholar
  4. Brüstle, A., Heink, S., Huber, M., Rosenplänter, C., Stadelmann, C., Yu, P., Arpaia, E., Mak, T.W., Kamradt, T., and Lohoff, M. (2007). The development of inflammatory T(H)-17 cells requires interferonregulatory factor 4. Nat Immunol 8, 958–966.CrossRefPubMedGoogle Scholar
  5. Chen, Z., Lin, F., Gao, Y., Li, Z., Zhang, J., Xing, Y., Deng, Z., Yao, Z., Tsun, A., and Li, B. (2011). FOXP3 and RORγt: transcriptional regulation of Treg and Th17. Int Immunopharmacol 11, 536–542.CrossRefPubMedGoogle Scholar
  6. Cobbold, S.P., Adams, E., Farquhar, C.A., Nolan, K.F., Howie, D., Lui, K.O., Fairchild, P.J., Mellor, A.L., Ron, D., and Waldmann, H. (2009). Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci U S A 106, 12055–12060.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Dang, E.V., Barbi, J., Yang, H.Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.R., et al. (2011). Control of T(H) 17/T(reg) balance by hypoxia-inducible factor 1. Cell 146, 772–784.PubMedCentralCrossRefPubMedGoogle Scholar
  8. Delgoffe, G.M., Pollizzi, K.N., Waickman, A.T., Heikamp, E., Meyers, D.J., Horton, M.R., Xiao, B., Worley, P.F., and Powell, J.D. (2011). The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12, 295–303.PubMedCentralCrossRefPubMedGoogle Scholar
  9. Finley, L.W., Carracedo, A., Lee, J., Souza, A., Egia, A., Zhang, J., Teruya-Feldstein, J., Moreira, P.I., Cardoso, S.M., Clish, C.B., et al. (2011). SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 19, 416–428.PubMedCentralCrossRefPubMedGoogle Scholar
  10. Haxhinasto, S., Mathis, D., and Benoist, C. (2008). The AKT-mTOR axis regulates de novo differentiation of CD4 + Foxp3 + cells. J Exp Med 205, 565–574.PubMedCentralCrossRefPubMedGoogle Scholar
  11. Kopf, H., de la Rosa, G.M., Howard, O.M., and Chen, X. (2007). Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol 7, 1819–1824.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Li, B., Samanta, A., Song, X., Furuuchi, K., Iacono, K.T., Kennedy, S., Katsumata, M., Saouaf, S.J., and Greene, M.I. (2006). FOXP3 ensembles in T-cell regulation. Immunol Rev 212, 99–113.CrossRefPubMedGoogle Scholar
  13. Li, B., Samanta, A., Song, X., Iacono, K.T., Bembas, K., Tao, R., Basu, S., Riley, J.L., Hancock, W.W., Shen, Y., et al. (2007). FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci U S A 104, 4571–4576.PubMedCentralCrossRefPubMedGoogle Scholar
  14. Mangan, P.R., Harrington, L.E., O’Quinn, D.B., Helms, W.S., Bullard, D.C., Elson, C.O., Hatton, R.D., Wahl, S.M., Schoeb, T.R., and Weaver, C.T. (2006). Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231–234.CrossRefPubMedGoogle Scholar
  15. Michalek, R.D., Gerriets, V.A., Jacobs, S.R., Macintyre, A.N., MacIver, N.J., Mason, E.F., Sullivan, S.A., Nichols, A.G., and Rathmell, J.C. (2011). Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186, 3299–3303.PubMedCentralCrossRefPubMedGoogle Scholar
  16. Okamoto, K., Iwai, Y., Oh-Hora, M., Yamamoto, M., Morio, T., Aoki, K., Ohya, K., Jetten, A.M., Akira, S., Muta, T., et al.(2010). IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors. Nature 464, 1381–1385.CrossRefPubMedGoogle Scholar
  17. Park, H., Li, Z., Yang, X.O., Chang, S.H., Nurieva, R., Wang, Y.H., Wang, Y., Hood, L., Zhu, Z., Tian, Q., et al. (2005). A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6, 1133–1141.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Schraml, B.U., Hildner, K., Ise, W., Lee, W.L., Smith, W.A., Solomon, B., Sahota, G., Sim, J., Mukasa, R., Cemerski, S., et al. (2009). The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460, 405–409.PubMedCentralPubMedGoogle Scholar
  19. Semenza, G.L., and Wang, G.L. (1992). A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12, 5447–5454.PubMedCentralCrossRefPubMedGoogle Scholar
  20. Shi, L.Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D.R., and Chi, H. (2011). HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208, 1367–1376.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Tong, X., Zhao, F., and Thompson, C.B. (2009). The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev 19, 32–37.PubMedCentralCrossRefPubMedGoogle Scholar
  22. van Loosdregt, J., Vercoulen, Y., Guichelaar, T., Gent, Y.Y., Beekman, J.M., van Beekum, O., Brenkman, A.B., Hijnen, D.J., Mutis, T., Kalkhoven, E., et al. (2010). Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115, 965–974.CrossRefPubMedGoogle Scholar
  23. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M., and Stockinger, B. (2006). TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189.CrossRefPubMedGoogle Scholar
  24. Weidemann, A., and Johnson, R.S. (2008). Biology of HIF-1alpha. Cell Death Differ 15, 621–627.CrossRefPubMedGoogle Scholar
  25. Zeiser, R., Leveson-Gower, D.B., Zambricki, E.A., Kambham, N., Beilhack, A., Loh, J., Hou, J.Z., and Negrin, R.S. (2008). Differential impact of mammalian target of rapamycin inhibition on CD4 + CD25 + Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 111, 453–462.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J.M., Chu, T.T., Corcoran, L., Treuting, P., Klein, U., and Rudensky, A.Y. (2009). Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458, 351–356.PubMedCentralCrossRefPubMedGoogle Scholar
  27. Zhou, L., Lopes, J.E., Chong, M.M., Ivanov, I.I., Min, R., Victora, G.D., Shen, Y., Du, J., Rubtsov, Y.P., Rudensky, A.Y., et al. (2008). TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453, 236–240.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina

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