Decline of FoxP3+ Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria

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In malaria endemic regions, immunity is slow to develop and does not provide substantial protection against reinfection. Rather, following repeated exposure, older children and adults eventually develop protection from most symptomatic manifestations of the infection. This may be due in part to the induction of immunoregulatory mechanisms by the P. falciparum parasite, such as FoxP3+ regulatory T cells (Tregs). Prior human studies have shown that Tregs are induced by malaria parasites both in vivo and in vitro, but the role of these cells in immunity in children who are chronically exposed to malaria remains unclear. In this study, we assessed the frequency and features of Tregs among children from areas of high malaria transmission in Uganda. We found that this regulatory T cell population declined markedly with increasing malaria episodes. This loss was associated with decreased expression of TNFR2, which is a protein implicated in stability of Tregs. Additionally, T cells from highly malaria exposed children demonstrated a reduced propensity to differentiate into Tregs following parasite stimulation. Together our data suggest that repeated episodes of malaria alter Treg homeostasis, which may influence the development of immunity to malaria in children.

Vyšlo v časopise: Decline of FoxP3+ Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005041
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005041

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1. Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420: 502–507. doi: 10.1038/nature01152 12466842

2. Belkaid Y, Blank RB, Suffia I (2006) Natural regulatory T cells and parasites: a common quest for host homeostasis. Immunol Rev 212: 287–300. doi: 10.1111/j.0105-2896.2006.00409.x 16903921

3. Velavan TP, Ojurongbe O (2011) Regulatory T cells and parasites. J Biomed Biotechnol 2011: 520940. doi: 10.1155/2011/520940 22262943

4. Walther M, Tongren JE, Andrews L, Korbel D, King E, et al. (2005) Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23: 287–296. doi: 10.1016/j.immuni.2005.08.006 16169501

5. Finney OC, Nwakanma D, Conway DJ, Walther M, Riley EM (2009) Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission. Eur J Immunol 39: 1288–1300. doi: 10.1002/eji.200839112 19338000

6. Walther M, Jeffries D, Finney OC, Njie M, Ebonyi A, et al. (2009) Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog 5: e1000364. doi: 10.1371/journal.ppat.1000364 19343213

7. Bueno LL, Morais CG, Araújo FF, Gomes JAS, Corrêa-Oliveira R, et al. (2010) Plasmodium vivax: induction of CD4+CD25+FoxP3+ regulatory T cells during infection are directly associated with level of circulating parasites. PLoS ONE 5: e9623. doi: 10.1371/journal.pone.0009623 20224778

8. Minigo G, Woodberry T, Piera KA, Salwati E, Tjitra E, et al. (2009) Parasite-dependent expansion of TNF receptor II-positive regulatory T cells with enhanced suppressive activity in adults with severe malaria. PLoS Pathog 5: e1000402. doi: 10.1371/journal.ppat.1000402 19390618

9. Scholzen A, Cooke BM, Plebanski M (2014) Plasmodium falciparum induces Foxp3hi CD4 T cells independent of surface PfEMP1 expression via small soluble parasite components. Front Microbiol 5: 200. doi: 10.3389/fmicb.2014.00200 24822053

10. Scholzen A, Mittag D, Rogerson SJ, Cooke BM, Plebanski M (2009) Plasmodium falciparum-mediated induction of human CD25Foxp3 CD4 T cells is independent of direct TCR stimulation and requires IL-2, IL-10 and TGFbeta. PLoS Pathog 5: e1000543. doi: 10.1371/journal.ppat.1000543 19680449

11. Clemente A, Caporale R, Sannella AR, Majori G, Severini C, et al. (2011) Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFβ-mediated signals. Cell Microbiol 13: 1328–1338. doi: 10.1111/j.1462-5822.2011.01622.x 21699642

12. Finney OC, Lawrence E, Gray AP, Njie M, Riley EM, et al. (2012) Freeze-thaw lysates of Plasmodium falciparum-infected red blood cells induce differentiation of functionally competent regulatory T cells from memory T cells. Eur J Immunol 42: 1767–1777. doi: 10.1002/eji.201142164 22585585

13. Finney OC, Riley EM, Walther M (2010) Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/-) ex vivo and after in vitro restimulation with malaria antigens. Eur J Immunol 40: 47–60. doi: 10.1002/eji.200939708 19877016

14. Todryk SM, Walther M, Bejon P, Hutchings C, Thompson FM, et al. (2009) Multiple functions of human T cells generated by experimental malaria challenge. Eur J Immunol 39: 3042–3051. doi: 10.1002/eji.200939434 19658096

15. Taylor MD, van der Werf N, Maizels RM (2012) T cells in helminth infection: the regulators and the regulated. Trends Immunol 33: 181–189. doi: 10.1016/j.it.2012.01.001 22398370

16. Todryk SM, Bejon P, Mwangi T, Plebanski M, Urban B, et al. (2008) Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans. PLoS ONE 3: e2027. doi: 10.1371/journal.pone.0002027 18446217

17. Kho S, Marfurt J, Noviyanti R, Kusuma A (2015) Preserved dendritic cell HLA-DR expression and reduced regulatory T cell activation in asymptomatic Plasmodium falciparum and P. vivax infection. Infection and …. doi: 10.1128/IAI.00226-15

18. Scholzen A, Minigo G, Plebanski M (2010) Heroes or villains? T regulatory cells in malaria infection. Trends Parasitol 26: 16–25. doi: 10.1016/j.pt.2009.10.004 19914134

19. Finney OC, Riley EM, Walther M (2010) Regulatory T cells in malaria—friend or foe? Trends Immunol 31: 63–70. doi: 10.1016/j.it.2009.12.002 20056484

20. Hisaeda H, Maekawa Y, Iwakawa D, Okada H, Himeno K, et al. (2004) Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat Med 10: 29–30. doi: 10.1038/nm975 14702631

21. Kamya MR, Arinaitwe E, Wanzira H, Katureebe A, Barusya C, et al. (2015) Malaria transmission, infection, and disease at three sites with varied transmission intensity in Uganda: implications for malaria control. Am J Trop Med Hyg 92: 903–912. doi: 10.4269/ajtmh.14-0312 25778501

22. Jagannathan P, Eccles-James I, Bowen K, Nankya F, Auma A, et al. (2014) IFNγ/IL-10 co-producing cells dominate the CD4 response to malaria in highly exposed children. PLoS Pathog 10: e1003864. doi: 10.1371/journal.ppat.1003864 24415936

23. Portugal S, Moebius J, Skinner J, Doumbo S, Doumtabe D, et al. (2014) Exposure-dependent control of malaria-induced inflammation in children. PLoS Pathog 10: e1004079. doi: 10.1371/journal.ppat.1004079 24743880

24. Gitau EN, Tuju J, Karanja H, Stevenson L, Requena P, et al. (2014) CD4+ T cell responses to the Plasmodium falciparum erythrocyte membrane protein 1 in children with mild malaria. J Immunol 192: 1753–1761. doi: 10.4049/jimmunol.1200547 24453249

25. Gitau EN, Tuju J, Stevenson L, Kimani E, Karanja H, et al. (2012) T-cell responses to the DBLα-tag, a short semi-conserved region of the Plasmodium falciparum membrane erythrocyte protein 1. PLoS ONE 7: e30095. doi: 10.1371/journal.pone.0030095 22272280

26. Wanzirah H, Tusting LS, Arinaitwe E, Katureebe A, Maxwell K, et al. (2015) Mind the gap: house structure and the risk of malaria in Uganda. PLoS ONE 10: e0117396. doi: 10.1371/journal.pone.0117396 25635688

27. Bisseye C, van der Sande M, Morgan WD, Holder AA, Pinder M, et al. (2009) Plasmodium falciparum infection of the placenta impacts on the T helper type 1 (Th1)/Th2 balance of neonatal T cells through CD4(+)CD25(+) forkhead box P3(+) regulatory T cells and interleukin-10. Clin Exp Immunol 158: 287–293. doi: 10.1111/j.1365-2249.2009.04014.x 19758375

28. Brustoski K, Moller U, Kramer M, Hartgers FC, Kremsner PG, et al. (2006) Reduced cord blood immune effector-cell responsiveness mediated by CD4+ cells induced in utero as a consequence of placental Plasmodium falciparum infection. J Infect Dis 193: 146–154. doi: 10.1086/498578 16323143

29. Mackroth MS, Malhotra I, Mungai P, Koech D, Muchiri E, et al. (2011) Human cord blood CD4+CD25hi regulatory T cells suppress prenatally acquired T cell responses to Plasmodium falciparum antigens. J Immunol 186: 2780–2791. doi: 10.4049/jimmunol.1001188 21278348

30. Flanagan KL, Halliday A, Burl S, Landgraf K, Jagne YJ, et al. (2010) The effect of placental malaria infection on cord blood and maternal immunoregulatory responses at birth. Eur J Immunol 40: 1062–1072. doi: 10.1002/eji.200939638 20039298

31. Chen X, Wu X, Zhou Q, Howard OMZ, Netea MG, et al. (2013) TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J Immunol 190: 1076–1084. doi: 10.4049/jimmunol.1202659 23277487

32. Okubo Y, Mera T, Wang L, Faustman DL (2013) Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2. Sci Rep 3: 3153. doi: 10.1038/srep03153 24193319

33. Chen X, Subleski JJ, Hamano R, Howard OMZ, Wiltrout RH, et al. (2010) Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood. Eur J Immunol 40: 1099–1106. doi: 10.1002/eji.200940022 20127680

34. Chen X, Subleski JJ, Kopf H, Howard OMZ, Männel DN, et al. (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. J Immunol 180: 6467–6471. doi: 10.4049/jimmunol.180.10.6467 18453563

35. Clemente AM, Severini C, Castronovo G, Tanturli M, Perissi E, et al. (2014) Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes. Microbes Infect 16: 778–787. doi: 10.1016/j.micinf.2014.08.002 25130316

36. Xing S, Fu J, Zhang Z, Gao Y, Jiao Y, et al. (2010) Increased turnover of FoxP3high regulatory T cells is associated with hyperactivation and disease progression of chronic HIV-1 infection. J Acquir Immune Defic Syndr 54: 455–462. doi: 10.1097/QAI.0b013e3181e453b9 20585263

37. Greenhouse B, Ho B, Hubbard A, Njama-Meya D, Narum DL, et al. (2011) Antibodies to Plasmodium falciparum antigens predict a higher risk of malaria but protection from symptoms once parasitemic. Journal of Infectious Diseases 204: 19–26. doi: 10.1093/infdis/jir223 21628654

38. Jagannathan P, Nankya F, Stoyanov C, Eccles-James I, Sikyomu E, et al. (2015) IFNγ Responses to Pre-erythrocytic and Blood-stage Malaria Antigens Exhibit Differential Associations With Past Exposure and Subsequent Protection. Journal of Infectious Diseases 211: 1987–1996. doi: 10.1093/infdis/jiu814 25520427

39. Jagannathan P, Kim CC, Greenhouse B, Nankya F, Bowen K, et al. (2014) Loss and dysfunction of Vδ2⁺ γδ T cells are associated with clinical tolerance to malaria. Science Translational Medicine 6: 251ra117. doi: 10.1126/scitranslmed.3009793 25163477

40. Omer FM, de Souza JB, Corran PH, Sultan AA, Riley EM (2003) Activation of transforming growth factor beta by malaria parasite-derived metalloproteinases and a thrombospondin-like molecule. J Exp Med 198: 1817–1827. doi: 10.1084/jem.20030713 14676296

41. Wan YY, Flavell RA (2007) Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445: 766–770. doi: 10.1038/nature05479 17220876

42. Zheng S-G, Wang J, Horwitz DA (2008) Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol 180: 7112–7116. 18490709

43. Koenen HJPM, Smeets RL, Vink PM, van Rijssen E, Boots AMH, et al. (2008) Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112: 2340–2352. doi: 10.1182/blood-2008-01-133967 18617638

44. Bailey-Bucktrout SL, Martínez-Llordella M, Zhou X, Anthony B, Rosenthal W, et al. (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39: 949–962. doi: 10.1016/j.immuni.2013.10.016 24238343

45. Li Z, Li D, Tsun A, Li B (2015) FOXP3(+) regulatory T cells and their functional regulation. Cell Mol Immunol. doi: 10.1038/cmi.2015.10

46. Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8: 277–284. doi: 10.1038/ni1437 17220892

47. Sakaguchi S, Vignali DAA, Rudensky AY, Niec RE, Waldmann H (2013) The plasticity and stability of regulatory T cells. Nat Rev Immunol 13: 461–467. doi: 10.1038/nri3464 23681097

48. Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, et al. (2012) Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36: 262–275. doi: 10.1016/j.immuni.2011.12.012 22326580

49. Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, et al. (2010) Stability of the regulatory T cell lineage in vivo. Science 329: 1667–1671. doi: 10.1126/science.1191996 20929851

50. Bailey-Bucktrout SL, Bluestone JA (2011) Regulatory T cells: stability revisited. Trends Immunol 32: 301–306. doi: 10.1016/j.it.2011.04.002 21620768

51. Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martínez-Llordella M, et al. (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10: 1000–1007. doi: 10.1038/ni.1774 19633673

52. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, et al. (2009) Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 106: 1903–1908. doi: 10.1073/pnas.0811556106 19174509

53. Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D, et al. (2009) Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31: 772–786. doi: 10.1016/j.immuni.2009.10.001 19896394

54. Hoffmann P, Boeld TJ, Eder R, Huehn J, Floess S, et al. (2009) Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur J Immunol 39: 1088–1097. doi: 10.1002/eji.200838904 19283780

55. Kleijwegt FS, Laban S, Duinkerken G, Joosten AM, Zaldumbide A, et al. (2010) Critical role for TNF in the induction of human antigen-specific regulatory T cells by tolerogenic dendritic cells. J Immunol 185: 1412–1418. doi: 10.4049/jimmunol.1000560 20574005

56. Boyle MJ, Jagannathan P, Bowen K, McIntyre TI, Vance HM, et al. (2015) Effector Phenotype of Plasmodium falciparum-Specific CD4+ T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations. Journal of Infectious Diseases. doi: 10.1093/infdis/jiv054

57. Jangpatarapongsa K, Chootong P, Sattabongkot J, Chotivanich K, Sirichaisinthop J, et al. (2008) Plasmodium vivax parasites alter the balance of myeloid and plasmacytoid dendritic cells and the induction of regulatory T cells. Eur J Immunol 38: 2697–2705. doi: 10.1002/eji.200838186 18825754

58. Doolan DL, Dobaño C, Baird JK (2009) Acquired immunity to malaria. Clinical Microbiology Reviews 22: 13–36–TableofContents. doi: 10.1128/CMR.00025-08 19136431

59. Bigira V, Kapisi J, Clark TD, Kinara S, Mwangwa F, et al. (2014) Protective efficacy and safety of three antimalarial regimens for the prevention of malaria in young ugandan children: a randomized controlled trial. PLoS Med 11: e1001689. doi: 10.1371/journal.pmed.1001689 25093754

60. Wanzira H, Kakuru A, Arinaitwe E, Bigira V, Muhindo MK, et al. (2014) Longitudinal outcomes in a cohort of Ugandan children randomized to artemether-lumefantrine versus dihydroartemisinin-piperaquine for the treatment of malaria. Clin Infect Dis 59: 509–516. doi: 10.1093/cid/ciu353 24825870

61. Schwartz A, Baidjoe A, Rosenthal PJ, Dorsey G, Bousema T, et al. (2015) The Effect of Storage and Extraction Methods on Amplification of Plasmodium falciparum DNA from Dried Blood Spots. Am J Trop Med Hyg 92: 922–925. doi: 10.4269/ajtmh.14-0602 25758652

62. Zeger SL, Liang KY (1986) Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42: 121–130. 3719049