Stability of Regulatory T Cells Undermined or Endorsed by Different Type-1 Cytokines

  • Silvia Piconese
  • Vincenzo BarnabaEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 850)


Regulatory T cells (Tregs) encompass an array of immunosuppressive cells responsible for the protection against exacerbated immune responses and the maintenance of tissue homeostasis. Various Treg subtypes, normally resident within distinct lymphoid and non-lymphoid tissues, can be recruited and expanded during inflammation, possibly undergoing functional and molecular re-programming. Generally, two processes have been reported in different settings of type-1 response: i) Treg subpopulations acquiring the ability to specifically suppress Th1 cells (called Th1-suppressing Tregs), and ii) Treg subsets rather polarizing into IFN-γ-producing (called Th1-like) Tregs.

Along the development of type-1 responses, Tregs are exposed to a variety of cytokines and other signals, exerting disparate activities. The combinatorial effects of typical Th1-driving cytokines, such as IL-12 (mostly produced by antigen-presenting cells during Th1 priming) and IFN-γ (mostly produced by pre-existing NK cells) lead to inhibition of Treg expansion and function, while promoting Th1-like Treg polarization. Conversely, cytokines produced at more advanced phases by Th1 effectors, such as IL-2, TNF-α and IFN-γ, promote Treg proliferation and/or Th1-suppressing Treg specialization. Some controversy exists around IL-27 and IFN-α, cytokines possibly released during bacterial or viral infections. Furthermore, cytokine signals can be finely tuned by the concomitant stimulation of costimulatory or coinhibitory receptors, such as OX40 and PD-1 respectively, within inflamed tissues.

A model may be envisaged of an alternate Treg response to type-1 cytokines, being hampered or boosted by early or late phase cytokines, respectively. Such regulation would unleash the development of protective type-1 immunity while constraining exacerbated Th1 responses, possibly causing immunopathology.


Th1 cells Regulatory T cells (Tregs) Th1-suppressing Th1-like Cytokine signals Type-1 cytokines CD4 T cells 


  1. Bacher, N., Raker, V., Hofmann, C., Graulich, E., Schwenk, M., Baumgrass, R., Bopp, T., Zechner, U., Merten, L., Becker, C., & Steinbrink, K. (2013). Interferon-alpha suppresses cAMP to disarm human regulatory T cells. Cancer Research, 73(18), 5647–5656. doi:10.1158/0008–5472.CAN-12-3788.CrossRefPubMedGoogle Scholar
  2. Barnaba, V. (2010). Hepatitis C virus infection: A “liaison a trois” amongst the virus, the host, and chronic low-level inflammation for human survival. Journal of Hepatology, 53(4), 752–761. doi:10.1016/j.jhep.2010.06.003.CrossRefPubMedGoogle Scholar
  3. Barnaba, V., & Schinzari, V. (2013). Induction, control, and plasticity of Treg cells: The immune regulatory network revised? European Journal of Immunology, 43(2), 318–322. doi:10.1002/eji.201243265.CrossRefPubMedGoogle Scholar
  4. Boyman, O., & Sprent, J. (2012). The role of interleukin-2 during homeostasis and activation of the immune system. Nature Reviews Immunology, 12(3), 180–190. doi:10.1038/nri3156.PubMedGoogle Scholar
  5. Burzyn, D., Benoist, C., & Mathis, D. (2013a). Regulatory T cells in nonlymphoid tissues. Nature Immunology, 14(10), 1007–1013. doi:10.1038/ni.2683.CrossRefPubMedGoogle Scholar
  6. Burzyn, D., Kuswanto, W., Kolodin, D., Shadrach, J. L., Cerletti, M., Jang, Y., Sefik, E., Tan, T. G., Wagers, A. J., Benoist, C., & Mathis, D. (2013b). A special population of regulatory T cells potentiates muscle repair. Cell, 155(6), 1282–1295. doi:10.1016/j.cell.2013.10.054.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Chen, X., Baumel, M., Mannel, D. N., Howard, O. M., & Oppenheim, J. J. (2007). Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+ CD25+ T regulatory cells. The Journal of Immunology, 179(1), 154–161.CrossRefPubMedGoogle Scholar
  8. Chen, X., Subleski, J. J., Kopf, H., Howard, O. M., Mannel, D. N., & Oppenheim, J. J. (2008). Cutting edge: Expression of TNFR2 defines a maximally suppressive subset of mouse CD4+CD25+FoxP3+ T regulatory cells: Applicability to tumor-infiltrating T regulatory cells. The Journal of Immunology, 180(10), 6467–6471.PubMedCentralCrossRefPubMedGoogle Scholar
  9. Chen, X., Subleski, J. J., Hamano, R., Howard, O. M., Wiltrout, R. H., & Oppenheim, J. J. (2010). Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood. European Journal of Immunology, 40(4), 1099–1106. doi:10.1002/eji.200940022.PubMedCentralCrossRefPubMedGoogle Scholar
  10. Chen, X., Wu, X., Zhou, Q., Howard, O. M., Netea, M. G., & Oppenheim, J. J. (2013). TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. The Journal of Immunology, 190(3), 1076–1084. doi:10.4049/jimmunol.1202659.PubMedCentralCrossRefPubMedGoogle Scholar
  11. Cheng, G., Yu, A., & Malek, T. R. (2011). T-cell tolerance and the multi-functional role of IL-2.R signaling in T-regulatory cells. Immunological Reviews, 241(1), 63–76. doi:10.1111/j.1600–065X.2011.01004.x.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Cipolletta, D., Feuerer, M., Li, A., Kamei, N., Lee, J., Shoelson, S. E., Benoist, C., & Mathis, D. (2012). PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 486(7404), 549–553. doi:10.1038/nature11132.PubMedCentralPubMedGoogle Scholar
  13. Di Sabatino, A., Biancheri, P., Piconese, S., Rosado, M. M., Ardizzone, S., Rovedatti, L., Ubezio, C., Massari, A., Sampietro, G. M., Foschi, D., Porro, G. B., Colombo, M. P., Carsetti, R., MacDonald, T. T., & Corazza, G. R. (2010). Peripheral regulatory T cells and serum transforming growth factor-beta: Relationship with clinical response to infliximab in Crohn’s disease. Inflammatory Bowel Diseases, 16(11), 1891–1897. doi:10.1002/ibd.21271.CrossRefPubMedGoogle Scholar
  14. Dominguez-Villar, M., Baecher-Allan, C. M., & Hafler, D. A. (2011). Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nature Medicine, 17(6), 673–675. doi:10.1038/nm.2389.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Du, W., Shen, Y. W., Lee, W. H., Wang, D., Paz, S., Kandeel, F., & Liu, C. P. (2013). Foxp3+ Treg expanded from patients with established diabetes reduce Helios expression while retaining normal function compared to healthy individuals. PLos One, 8(2), e56209. doi:10.1371/journal.pone.0056209.PubMedCentralCrossRefPubMedGoogle Scholar
  16. Franceschini, D., Paroli, M., Francavilla, V., Videtta, M., Morrone, S., Labbadia, G., Cerino, A., Mondelli, M. U., & Barnaba, V. (2009). PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. Journal of Clinical Investigation, 119(3), 551–564. doi:10.1172/JCI36604.PubMedCentralCrossRefPubMedGoogle Scholar
  17. Gonzalez-Navajas, J. M., Lee, J., David, M., & Raz, E. (2012). Immunomodulatory functions of type I interferons. Nature Reviews Immunology, 12(2), 125–135. doi:10.1038/nri3133.PubMedCentralPubMedGoogle Scholar
  18. Grinberg-Bleyer, Y., Saadoun, D., Baeyens, A., Billiard, F., Goldstein, J. D., Gregoire, S., Martin, G. H., Elhage, R., Derian, N., Carpentier, W., Marodon, G., Klatzmann, D., Piaggio, E., & Salomon, B. L. (2010). Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. Journal of Clinical Investigation, 120(12), 4558–4568. doi:10.1172/JCI42945.PubMedCentralCrossRefPubMedGoogle Scholar
  19. Griseri, T., Asquith, M., Thompson, C., & Powrie, F. (2010). OX40 is required for regulatory T cell-mediated control of colitis. The Journal of Experimental Medicine, 207(4), 699–709. doi:10.1084/jem.20091618.PubMedCentralCrossRefPubMedGoogle Scholar
  20. Hall, A. O., Beiting, D. P., Tato, C., John, B., Oldenhove, G., Lombana, C. G., Pritchard, G. H., Silver, J. S., Bouladoux, N., Stumhofer, J. S., Harris, T. H., Grainger, J., Wojno, E. D., Wagage, S., Roos, D. S., Scott, P., Turka, L. A., Cherry, S., Reiner, S. L., Cua, D., Belkaid, Y., Elloso, M. M., & Hunter, C. A. (2012). The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity, 37(3), 511–523. doi:10.1016/j.immuni.2012.06.014.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Hamano, R., Huang, J., Yoshimura, T., Oppenheim, J. J., Chen, X. (2011). TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40. European Journal of Immunology, 41(7), 2010–2020. doi:10.1002/eji.201041205.PubMedCentralCrossRefPubMedGoogle Scholar
  22. Hippen, K. L., Harker-Murray, P., Porter, S. B., Merkel, S. C., Londer, A., Taylor, D. K., Bina, M., Panoskaltsis-Mortari, A., Rubinstein, P., Van Rooijen, N., Golovina, T. N., Suhoski, M. M., Miller, J. S., Wagner, J. E., June, C. H., Riley, J. L., & Blazar, B. R. (2008). Umbilical cord blood regulatory T-cell expansion and functional effects of tumor necrosis factor receptor family members OX40 and 4-1BB expressed on artificial antigen-presenting cells. Blood, 112(7), 2847–2857. doi:10.1182/blood-2008-01-132951.PubMedCentralCrossRefPubMedGoogle Scholar
  23. Hunter, C. A., & Kastelein, R. (2012). Interleukin-27: Balancing protective and pathological immunity. Immunity, 37(6), 960–969. doi:10.1016/j.immuni.2012.11.003.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B, & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature Immunology, 10(6), 595–602. doi:10.1038/ni.1731.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Koch, M. A., Thomas, K. R., Perdue, N. R., Smigiel, K. S., Srivastava, S., & Campbell, D. J. (2012). T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity, 37(3), 501–510. doi:10.1016/j.immuni.2012.05.031.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Koenecke, C., Lee, C. W., Thamm, K., Fohse, L., Schafferus, M., Mittrucker, H. W., Floess, S., Huehn, J., Ganser, A., Forster, R., & Prinz, I. (2012). IFN-gamma production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease. The Journal of Immunology, 189(6), 2890–2896. doi:10.4049/jimmunol.1200413.CrossRefPubMedGoogle Scholar
  27. Lazarevic, V., Glimcher, L. H., & Lord, G. M. (2013). T-bet: A bridge between innate and adaptive immunity. Nature Reviews Immunology, 13(11), 777–789. doi:10.1038/nri3536.CrossRefPubMedGoogle Scholar
  28. Le Buanec, H., Gougeon, M. L., Mathian, A., Lebon, P., Dupont, J. M., Peltre, G., Hemon, P., Schmid, M., Bizzini, B., Kunding, T., Burny, A., Bensussan, A., Amoura, Z., Gallo, R. C., & Zagury, D. (2011). IFN-alpha and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells. Proceedings of the National Academy of Sciences of the United States of America, 108(47), 18995–19000. doi:10.1073/pnas.1113301108.Google Scholar
  29. Lee, S. E., Li, X., Kim, J. C., Lee, J., Gonzalez-Navajas, J. M., Hong, S. H., Park, I. K., Rhee, J. H., & Raz, E. (2012). Type I interferons maintain Foxp3 expression and T-regulatory cell functions under inflammatory conditions in mice. Gastroenterology, 143(1), 145–154. doi:10.1053/j.gastro.2012.03.042.PubMedCentralCrossRefPubMedGoogle Scholar
  30. Lu, L. F., Boldin, M. P., Chaudhry, A., Lin, L. L., Taganov, K. D., Hanada, T., Yoshimura, A., Baltimore, D., & Rudensky, A. Y. (2010). Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell, 142(6), 914–929. doi:10.1016/j.cell.2010.08.012.PubMedCentralCrossRefPubMedGoogle Scholar
  31. Mahmud, S. A., Manlove, L. S., Schmitz, H. M., Xing, Y., Wang, Y., Owen, D. L., Schenkel, J. M., Boomer, J. S., Green, J. M., Yagita, H., Chi, H., Hogquist, K. A., & Farrar, M. A. (2014). Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nature Immunology, 15(5), 473–481. doi:10.1038/ni.2849.PubMedCentralCrossRefPubMedGoogle Scholar
  32. Malek, T. R., & Bayer, A. L. (2004). Tolerance, not immunity, crucially depends on IL-2. Nature Reviews Immunology, 4(9), 665–674. doi:10.1038/nri1435.CrossRefPubMedGoogle Scholar
  33. McClymont, S. A., Putnam, A. L., Lee, M. R., Esensten, J. H., Liu, W., Hulme, M. A., Hoffmuller, U., Baron, U., Olek, S., Bluestone, J. A., Brusko, T. M. (2011). Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. The Journal of Immunology, 186(7), 3918–3926. doi:10.4049/jimmunol.1003099.PubMedCentralCrossRefPubMedGoogle Scholar
  34. Nadkarni, S., Mauri, C., & Ehrenstein, M. R. (2007). Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. The Journal of Experimental Medicine, 204(1), 33–39. doi:10.1084/jem.20061531.PubMedCentralCrossRefPubMedGoogle Scholar
  35. Nagar, M., Jacob-Hirsch, J., Vernitsky, H., Berkun, Y., Ben-Horin, S., Amariglio, N., Bank, I., Kloog, Y., Rechavi, G., & Goldstein, I. (2010). TNF activates a NF-kappaBregulated cellular program in human CD45RA-regulatory T cells that modulates their suppressive function. The Journal of Immunology, 184(7), 3570–3581. doi:10.4049/jimmunol.0902070.CrossRefPubMedGoogle Scholar
  36. Nie, H., Zheng, Y., Li, R., Guo, T. B., He, D., Fang, L., Liu, X., Xiao, L., Chen, X., Wan, B., Chin, Y. E., & Zhang, J. Z. (2013). Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nature Medicine, 19(3), 322–328. doi:10.1038/nm.3085.CrossRefPubMedGoogle Scholar
  37. Niesner, U., Albrecht, I., Janke, M., Doebis, C., Loddenkemper, C., Lexberg, M. H., Eulenburg, K., Kreher, S., Koeck, J., Baumgrass, R., Bonhagen, K., Kamradt, T., Enghard, P., Humrich, J. Y., Rutz, S., Schulze-Topphoff, U., Aktas, O., Bartfeld, S., Radbruch, H., Hegazy, A. N., Lohning, M., Baumgart, D. C., Duchmann, R., Rudwaleit, M., Haupl, T., Gitelman, I., Krenn, V., Gruen, J., Sieper, J., Zeitz, M., Wiedenmann, B., Zipp, F., Hamann, A., Janitz, M., Scheffold, A., Burmester, G. R., Chang, H. D., & Radbruch, A. (2008). Autoregulation of Th1-mediated inflammation by twist1. The Journal of Experimental Medicine, 205(8), 1889–1901. doi:10.1084/jem.20072468.PubMedCentralCrossRefPubMedGoogle Scholar
  38. O’Garra, A., & Vieira, P. (2007). T(H)1 cells control themselves by producing interleukin 10. Nature Reviews Immunology, 7(6), 425–428. doi:10.1038/nri2097.CrossRefPubMedGoogle Scholar
  39. Oldenhove, G., Bouladoux, N., Wohlfert, E. A., Hall, J. A., Chou, D., Dos Santos, L., O’Brien, S., Blank, R., Lamb, E., Natarajan, S., Kastenmayer, R., Hunter, C., Grigg, M. E., & Belkaid, Y. (2009). Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity, 31(5), 772–786. doi:10.1016/j.immuni.2009.10.001.PubMedCentralCrossRefPubMedGoogle Scholar
  40. Pace, L., Vitale, S., Dettori, B., Palombi, C., La Sorsa, V., Belardelli, F., Proietti, E., & Doria, G. (2010). APC activation by IFN-alpha decreases regulatory T cell and enhances Th cell functions. The Journal of Immunology, 184(11), 5969–5979. doi:10.4049/jimmunol.0900526.CrossRefPubMedGoogle Scholar
  41. Piconese, S., Pittoni, P., Burocchi, A., Gorzanelli, A., Care, A., Tripodo, C., & Colombo, M. P. (2010). A non-redundant role for OX40 in the competitive fitness of Treg in response to IL-2. European Journal of Immunology, 40(10), 2902–2913. doi:10.1002/eji.201040505.CrossRefPubMedGoogle Scholar
  42. Piconese, S., Timperi, E., Pacella, I., Schinzari, V., Tripodo, C., Rossi, M., Guglielmo, N., Mennini, G., Grazi, G. L., Di Filippo, S., Brozzetti, S., Fazzi, K., Antonelli, G., Lozzi, M. A., Sanchez, M., & Barnaba, V. (2014). Human OX40 tunes the function of regulatory T cells in tumor and non-tumor areas of HCV-infected liver tissue. Hepatology. doi:10.1002/hep.27188.Google Scholar
  43. Redjimi, N., Raffin, C., Raimbaud, I., Pignon, P., Matsuzaki, J., Odunsi, K., Valmori, D., & Ayyoub, M. (2012). CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Research, 72(17), 43514360. doi:10.1158/0008-5472.CAN-12-0579.CrossRefGoogle Scholar
  44. Ruby, C. E., Yates, M. A., Hirschhorn-Cymerman, D., Chlebeck, P., Wolchok, J. D., Houghton, A. N., Offner, H., & Weinberg, A. D. (2009). Cutting Edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. The Journal of Immunology, 183(8), 4853–4857. doi:10.4049/jimmunol.0901112.CrossRefPubMedGoogle Scholar
  45. Sage, P. T., Francisco, L. M., Carman, C. V., & Sharpe, A. H. (2013). The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nature Immunology, 14(2), 152–161. doi:10.1038/ni.2496.PubMedCentralCrossRefPubMedGoogle Scholar
  46. Shafiani, S., Dinh, C., Ertelt, J. M., Moguche, A. O., Siddiqui, I., Smigiel, K. S., Sharma, P., Campbell, D. J., Way, S. S., & Urdahl, K. B. (2013). Pathogen-specific Treg cells expand early during mycobacterium tuberculosis infection but are later eliminated in response to Interleukin-12. Immunity, 38(6), 1261–1270. doi:10.1016/j.immuni.2013.06.003.CrossRefPubMedGoogle Scholar
  47. Smigiel, K. S., Srivastava, S., Stolley, J. M., & Campbell, D. J. (2014). Regulatory T-cell homeostasis: Steady-state maintenance and modulation during inflammation. Immunological Reviews, 259(1), 40–59. doi:10.1111/imr.12170.PubMedCentralCrossRefPubMedGoogle Scholar
  48. Srivastava, S., Koch, M. A., Pepper, M., & Campbell, D. J. (2014). Type I interferons directly inhibit regulatory T cells to allow optimal antiviral T cell responses during acute LCMV infection. The Journal of Experimental Medicine, 211(5), 961–974. doi:10.1084/jem.20131556.PubMedCentralCrossRefPubMedGoogle Scholar
  49. Stewart, C. A., Metheny, H., Iida, N., Smith, L., Hanson, M., Steinhagen, F., Leighty, R. M., Roers, A., Karp, C. L., Muller, W., & Trinchieri, G. (2013). Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. Journal of Clinical Investigation, 123(11), 4859–4874. doi:10.1172/JCI65180.PubMedCentralCrossRefPubMedGoogle Scholar
  50. Trinchieri, G. (2010). Type I interferon: Friend or foe? The Journal of Experimental Medicine, 207(10), 2053–2063. doi:10.1084/jem.20101664.PubMedCentralCrossRefPubMedGoogle Scholar
  51. Xiao, X., Gong, W., Demirci, G., Liu, W., Spoerl, S., Chu, X., Bishop, D. K., Turka, L. A., & Li, X. C. (2012). New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. The Journal of Immunology, 188(2), 892–901. doi:10.4049/jimmunol.1101373.PubMedCentralCrossRefPubMedGoogle Scholar
  52. Zhao, J., & Perlman, S. (2012). Differential effects of IL-12 on Tregs and non-Treg T cells: Roles of IFN-gamma, IL-2 and IL-2R. PLos One, 7(9), e46241. doi:10.1371/journal.pone.0046241.PubMedCentralCrossRefPubMedGoogle Scholar
  53. Zhao, J., Fett, C., Trandem, K., Fleming, E., & Perlman, S. (2011). IFN-gamma-and IL-10expressing virus epitope-specific Foxp3(+) T reg cells in the central nervous system during encephalomyelitis. The Journal of Experimental Medicine, 208(8), 1571–1577. doi:10.1084/jem.20110236.PubMedCentralCrossRefPubMedGoogle Scholar
  54. Zhong, H., & Yazdanbakhsh, K. (2013). Differential control of Helios(+/-) Treg development by monocyte subsets through disparate inflammatory cytokines. Blood, 121(13), 2494–2502. doi:10.1182/blood-2012-11-469122.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Istituto Pasteur -Fondazione Cenci BolognettiRomeItaly
  2. 2.Dipartimento di Medicina Interna e Specialità MedicheSapienza Università di RomaRomeItaly

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