Volume 98 Number 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Immunoregulation is considered a common feature of infections, and elevated levels of T regulatory (Treg) lymphocytes have been reported during chronic human schistosomiasis. We now report that the removal of Treg (CD4+/CD25/CD127 lymphocytes) from peripheral blood mononuclear cells (PBMCs) of –infected individuals leads to increased levels of phytohemagglutinin (PHA)-stimulated interferon gamma (IFNγ) production and decreased interleukin-10 (IL-10) responses. Exposure to schistosome antigens did not result in measurable IFNγ by either PBMC or Treg-depleted populations. Interleukin-10 responses to soluble egg antigens (SEA) by PBMC were unchanged by Treg depletion, but the depletion of Treg greatly decreased IL-10 production to soluble worm antigenic preparation (SWAP). Proliferative responses to PHA increased upon Treg removal, but responses to SEA or SWAP did not, unless only initially low responders were evaluated. Addition of anti-IL-10 increased PBMC proliferative responses to either SEA or SWAP, but did not alter responses by Treg-depleted cells. Blockade by anti-transforming growth factor-beta (TGF-β) increased SEA but not SWAP proliferative responses by PBMC, whereas anti-TGF-β increased both SEA- and SWAP-stimulated responses by Treg-depleted cultures. Addition of both anti-IL-10 and anti-TGF-β to PBMC or Treg-depleted populations increased proliferation of both populations to either SEA or SWAP. These studies demonstrate that Treg appear to produce much of the antigen-stimulated IL-10, but other cell types or subsets of Treg may produce much of the TGF-β. The elevated levels of Treg seen in chronic schistosomiasis appear functional and involve IL-10 and TGF-β in antigen-specific immunoregulation perhaps leading to regulation of immunopathology and/or possibly decreased immunoprotective responses.

[open-access] This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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  1. Colley DG, Bustinduy AL, Secor WE, King CH, , 2014. Human schistosomiasis. Lancet 383: 22532264.
  2. Romano A, 2016. FOXP3+ regulatory T cells in hepatic fibrosis and splenomegaly caused by Schistosoma japonicum: the spleen may be a major source of Tregs in subjects with splenomegaly. PLoS Negl Trop Dis 10: e0004306.
  3. Wilson S, Jones FM, Kenty LC, Mwatha JK, Kimani G, Kariuki HC, Dunne DW, , 2014. Posttreatment changes in cytokines induced by Schistosoma mansoni egg and worm antigens: dissociation of immunity- and morbidity-associated type 2 responses. J Infect Dis 209: 17921800.
  4. Nausch N, Midzi N, Mduluza T, Maizels RM, Mutapi F, , 2011. Regulatory and activated T cells in human Schistosoma haematobium infections. PLoS One 6: e16860.
  5. Joseph S, 2004. Increases in human T helper 2 cytokine responses to Schistosoma mansoni worm and worm‐tegument antigens are induced by treatment with praziquantel. J Infect Dis 190: 835842.
  6. Silveira AM, 2004. Human schistosomiasis mansoni: intensity of infection differentially affects the production of interleukin-10, interferon-gamma and interleukin-13 by soluble egg antigen or adult worm antigen stimulated cultures. Trans R Soc Trop Med Hyg 98: 514519.
  7. Roberts M, Butterworth AE, Kimani G, Kamau T, Fulford AJ, Dunne DW, Ouma JH, Sturrock RF, , 1993. Immunity after treatment of human schistosomiasis: association between cellular responses and resistance to reinfection. Infect Immun 61: 49844993.
  8. Rodríguez-Perea AL, Arcia ED, Rueda CM, Velilla PA, , 2016. Phenotypical characterization of regulatory T cells in humans and rodents. Clin Exp Immunol 185: 281291.
  9. Miyara M, Sakaguchi S, , 2011. Human FoxP3(+) CD4(+) regulatory T cells: their knowns and unknowns. Immunol Cell Biol 89: 346351.
  10. Roncador G, 2005. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol 35: 16811691.
  11. Sakaguchi S, , 2000. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101: 455458.
  12. Schmiedel Y, Mombo-Ngoma G, Labuda LA, Janse JJ, de Gier B, Adegnika AA, Issifou S, Kremsner PG, Smits HH, Yazdanbakhsh M, , 2015. CD4+CD25hiFOXp3+ regulatory T cells and cytokine responses in human schistosomiasis before and after treatment with praziquantel. PLoS Negl Trop Dis 9: e0003995.
  13. Watanabe K, Mwinzi PNM, Black CL, Muok EMO, Karanja DMS, Secor WE, Colley DG, , 2007. T regulatory cell levels decrease in people infected with Schistosoma mansoni on effective treatment. Am J Trop Med Hyg 77: 676682.
  14. Roncarolo MG, Gregori S, , 2008. Is FOXP3 a bona fide marker for human regulatory T cells? Eur J Immunol 38: 925927.
  15. Hartigan-O’Connor DJ, Poon C, Sinclair E, McCune JM, , 2007. Human CD4+ regulatory T cells express lower levels of the IL-7 receptor alpha chain (CD127), allowing consistent identification and sorting of live cells. J Immunol Methods 319: 4152.
  16. Black CL, Mwinzi PNM, Muok EMO, Abudho B, Fitzsimmons CM, Dunne DW, Karanja DMS, Secor WE, Colley DG, , 2010. Influence of exposure history on the immunology and development of resistance to human Schistosomiasis mansoni. PLoS Negl Trop Dis 4: e637.
  17. Mwinzi PNM, Ganley-Leal L, Black CL, Secor WE, Karanja DMS, Colley DG, , 2009. Circulating CD23+ B cell subset correlates with the development of resistance to Schistosoma mansoni reinfection in occupationally exposed adults who have undergone multiple treatments. J Infect Dis 199: 272279.
  18. Karanja DMS, Hightower AW, Colley DG, Mwinzi PNM, Galil K, Andove J, Secor WE, , 2002. Resistance to reinfection with Schistosoma mansoni in occupationally exposed adults and effect of HIV-1 co-infection on susceptibility to schistosomiasis: a longitudinal study. Lancet 360: 592596.
  19. Katz N, Chaves A, Pellegrino J, , 1972. A simple device for quantitative stool thick-smear technique in Schistosomiasis mansoni. Rev Inst Med Trop São Paulo 14: 397400.
  20. WHO, 2013. Schistosomiasis: Progress Report 2001–2011, Strategic Plan 2012–2020. Geneva, Switzerland: World Health Organization.
  21. Colley DG, Cook JA, Freeman GL, Bartholomew RK, Jordan P, , 1977. Immune responses during human schistosomiasis mansoni: I. In vitro lymphocyte blastogenic responses to heterogeneous antigenic preparations from schistosome kggs, worms and cercariae. Int Arch Allergy Immunol 53: 420433.
  22. Boros DL, Warren KS, , 1970. Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs. J Exp Med 132: 488507.
  23. Sakaguchi S, Wing K, Miyara M, , 2007. Regulatory T cells—a brief history and perspective. Eur J Immunol 37 (Suppl 1): S116S123.
  24. Schmetterer KG, Neunkirchner A, Pickl WF, , 2012. Naturally occurring regulatory T cells: markers, mechanisms, and manipulation. FASEB J 26: 22532276.
  25. Dock J, Hultin L, Hultin P, Elliot J, Yang OO, Anton PA, Jamieson BD, Effros RB, , 2017. Human immune compartment comparisons: optimization of proliferative assays for blood and gut T lymphocytes. J Immunol Methods 445: 7787.
  26. Ndayishimiye O, Ortu G, Soares Magalhaes RJ, Clements A, Willems J, Whitton J, Lancaster W, Hopkins A, Fenwick A, , 2014. Control of neglected tropical diseases in Burundi: partnerships, achievements, challenges, and lessons learned after four years of programme implementation. PLoS Negl Trop Dis 8: e2684.
  27. Hanson C, Weaver A, Zoerhoff KL, Kabore A, Linehan M, Doherty A, Engels D, Savioli L, Ottesen EA, , 2012. Integrated implementation of programs targeting neglected tropical diseases through preventive chemotherapy: identifying best practices to roll out programs at national scale. Am J Trop Med Hyg 86: 508513.
  28. Zhang Y, MacArthur C, Mubila L, Baker S, , 2010. Control of neglected tropical diseases needs a long-term commitment. BMC Med 8: 67.
  29. Fenwick A, 2009. The schistosomiasis control initiative (SCI): rationale, development and implementation from 2002–2008. Parasitology 136: 17191730.
  30. De Moira AP, Jones FM, Wilson S, Tukahebwa E, Fitzsimmons CM, Mwatha JK, Bethony JM, Kabatereine NB, Dunnea DW, , 2013. Effects of treatment on IgE responses against parasite allergen-like proteins and immunit to reinfection in childhood schistosome and hookworm coinfections. Infect Immun 81: 2332.
  31. Bourke CD, Nausch N, Rujeni N, Appleby LJ, Mitchell KM, Midzi N, Mduluza T, Mutapi F, , 2013. Integrated analysis of innate, Th1, Th2, Th17, and regulatory cytokines identifies changes in immune polarisation following treatment of human schistosomiasis. J Infect Dis 208: 159169.
  32. Wilson MS, Cheever AW, White SD, Thompson RW, Wynn TA, , 2011. IL-10 blocks the development of resistance to re-infection with Schistosoma mansoni. PLoS Pathog 7: e1002171.
  33. Vereecken K, Naus CWA, Polman K, Scott JT, Diop M, Gryseels B, Kestens L, , 2007. Associations between specific antibody responses and resistance to reinfection in a Senegalese population recently exposed to Schistosoma mansoni. Trop Med Int Health 12: 431444.
  34. Colley DG, Secor WE, , 2014. Immunology of human schistosomiasis. Parasite Immunol 36: 347357.
  35. Corrêa-Oliveira R, 1998. Cytokines as determinants of resistance and pathology in human Schistosoma mansoni infection. Braz J Med Biol Res 31: 171177.
  36. van den Biggelaar AHJ, Borrmann S, Kremsner P, Yazdanbakhsh M, , 2002. Immune responses induced by repeated treatment do not result in protective immunity to Schistosoma haematobium: interleukin (IL)-5 and IL-10 responses. J Infect Dis 186: 14741482.
  37. Gazzinelli G, Montesano M, , 1987. Immune response in different clinical groups of schistosomiasis patients. Memórias do Inst 82 (Suppl 4): 95100.
  38. Colley DG, Garcia AA, Lambertucci JR, Parra JC, Katz N, Rocha RS, Gazzinelli G, , 1986. Immune responses during human schistosomiasis. XII. Differential responsiveness in patients with hepatosplenic disease. Am J Trop Med Hyg 35: 793802.
  39. Montenegro SM, 1999. Cytokine production in acute versus chronic human Schistosomiasis mansoni: the cross-regulatory role of interferon-gamma and interleukin-10 in the responses of peripheral blood mononuclear cells and splenocytes to parasite antigens. J Infect Dis 179: 15021514.
  40. Grogan JL, Kremsner PG, Deelder AM, Yazdanbakhsh M, , 1998. The effect of anti-IL-10 on proliferation and cytokine production in human schistosomiasis: fresh versus cryopreserved cells. Parasite Immunol 20: 345349.
  41. Malaquias LC, Falcão PL, Silveira AM, Gazzinelli G, Prata A, Coffman RL, Pizziolo V, Souza CP, Colley DG, Correa-Oliveira R, , 1997. Cytokine regulation of human immune response to Schistosoma mansoni: analysis of the role of IL-4, IL-5 and IL-10 on peripheral blood mononuclear cell responses. Scand J Immunol 46: 393398.
  42. Araújo M, 1996. Evidence of a T helper type 2 activation in human schistosomiasis. Eur J Immunol 26: 13991403.
  43. King CL, 1996. Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J Immunol 156: 47154721.
  44. Tran DQ, , 2012. TGF-β: the sword, the wand, and the shield of FOXP3(+) regulatory T cells. J Mol Cell Biol 4: 2937.
  45. Kochetkova I, Thornburg T, Callis G, Pascual DW, , 2011. Segregated regulatory CD39+CD4+ T cell function: TGF-β-producing Foxp3- and IL-10-producing Foxp3+ cells are interdependent for protection against collagen-induced arthritis. J Immunol 187: 46544666.
  46. Hussain S, Paterson Y, , 2004. CD4+CD25+ regulatory T cells that secrete TGFβ and IL-10 are preferentially induced by a vaccine vector. J Immunother 27: 339346.
  47. Zhang X, Koldzic DN, Izikson L, Reddy J, Nazareno RF, Sakaguchi S, Kuchroo VK, Weiner HL, , 2004. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int Immunol 16: 249256.
  48. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA, , 2006. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24: 99146.
  49. Omer FM, Kurtzhals JAL, Riley EM, , 2000. Maintaining the immunological balance in parasitic infections: a role for TGF-β? Parasitol Today 16: 1823.
  50. Reed SG, , 1999. TGF-beta in infections and infectious diseases. Microbes Infect 1: 13131325.
  51. Akdis M, 2016. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: receptors, functions, and roles in diseases. J Allergy Clin Immunol 138: 9841010.
  52. van der Vlugt LE, Zinsou JF, Ozir-Fazalalikhan A, Kremsner PG, Yazdanbakhsh M, Adegnika AA, Smits HH, , 2014. Interleukin 10 (IL-10)–producing CD1dhi regulatory B cells from Schistosoma haematobium–infected individuals induce IL-10–positive T cells and suppress effector T-cell cytokines. J Infect Dis 210: 12071216.
  53. Leavy O, , 2010. Regulatory T cells: CD8+ TReg cells join the fold. Nat Rev Immunol 10: 680681.
  54. Colley DG, Barsoum IS, Dahawi HSS, Gamil F, Habib M, El Alamy MA, , 1986. Immune responses and immunoregulation in relation to human schistosomiasis in Egypt. III. Immunity and longitudinal studies of in vitro responsiveness after treatment. Trans R Soc Trop Med Hyg 80: 952957.
  55. Oliveira LFA, Moreno EC, Gazzinelli G, Silveira AMS, Gazzinelli A, Loverde P, Leite PM, , 2006. Cytokine production associated with periportal fibrosis during chronic schistosomiasis mansoni in humans. Infect Immun 74: 12151221.

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  • Received : 11 Dec 2017
  • Accepted : 20 Feb 2018

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