Helminth Infection and Commensal Microbiota Drive Early IL-10 Production in the Skin by CD4 T Cells That Are Functionally Suppressive

English version České info

The skin is a major barrier protecting the host from pathogen infection, but is also a site for immune regulation. Using a murine model of repeated percutaneous exposure to infectious Schistosoma mansoni cercariae, we show that, in the skin, CD4+ T cells that do not express markers of conventional regulatory T cells are the main early source of immunoregulatory IL-10 and are functionally suppressive of adaptive immune responses. We demonstrate that the production of regulatory IL-10 in the skin is greatly enhanced after repeated schistosome infection compared to levels present after a single infection and that it limits both neutrophil recruitment and local CD4+ T cell proliferation, thereby preventing excessive inflammation and tissue damage. Initially (day 1), IL-10 producing CD4+ T cells are reactive towards skin commensal bacteria, although over succeeding days they progressively become specific for schistosome antigens. Consequently, our findings highlight a role for early IL-10 produced by dermal CD4+ T cells to mediate immune regulation in advance of later stage chronic infection conventionally associated with the presence of IL-10. Our work provides a mechanistic insight into the triggers of early IL-10 production at barrier sites like the skin, and suggests how tolerance and pathogen clearance might be co-regulated early after exposure to infectious agents.

Vyšlo v časopise: Helminth Infection and Commensal Microbiota Drive Early IL-10 Production in the Skin by CD4 T Cells That Are Functionally Suppressive. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004841
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004841

Souhrn

Zdroje

1. Rudikoff D, Lebwohl M (1998) Atopic dermatitis. Lancet 351: 1715–1721. 9734903

2. Kedzierski L, Evans KJ (2014) Immune responses during cutaneous and visceral leishmaniasis. Parasitology: 1–19.

3. Hoerauf A, Pfarr K, Mand S, Debrah AY, Specht S (2011) Filariasis in Africa—treatment challenges and prospects. Clin Microbiol Infect 17: 977–985. doi: 10.1111/j.1469-0691.2011.03586.x 21722251

4. Loukas A, Prociv P (2001) Immune responses in hookworm infections. Clin Microbiol Rev 14: 689–703, table of contents. 11585781

5. Paveley RA, Aynsley SA, Cook PC, Turner JD, Mountford AP (2009) Fluorescent imaging of antigen released by a skin-invading helminth reveals differential uptake and activation profiles by antigen presenting cells. PLoS Negl Trop Dis 3: e528. doi: 10.1371/journal.pntd.0000528 19829705

6. Loser K, Beissert S (2007) Dendritic cells and T cells in the regulation of cutaneous immunity. Adv Dermatol 23: 307–333. 18159907

7. Fahl SP, Coffey F, Wiest DL (2014) Origins of gammadelta T Cell Effector Subsets: A Riddle Wrapped in an Enigma. J Immunol 193: 4289–4294. doi: 10.4049/jimmunol.1401813 25326547

8. Roediger B, Kyle R, Yip KH, Sumaria N, Guy TV, et al. (2013) Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol 14: 564–573. doi: 10.1038/ni.2584 23603794

9. Heath WR, Carbone FR (2013) The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells. Nat Immunol 14: 978–985. doi: 10.1038/ni.2680 24048119

10. Pasparakis M, Haase I, Nestle FO (2014) Mechanisms regulating skin immunity and inflammation. Nat Rev Immunol 14: 289–301. doi: 10.1038/nri3646 24722477

11. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ (2009) Skin immune sentinels in health and disease. Nat Rev Immunol 9: 679–691. doi: 10.1038/nri2622 19763149

12. Belkaid Y, Naik S (2013) Compartmentalized and systemic control of tissue immunity by commensals. Nat Immunol 14: 646–653. doi: 10.1038/ni.2604 23778791

13. Grice EA, Segre JA (2011) The skin microbiome. Nat Rev Microbiol 9: 244–253. doi: 10.1038/nrmicro2537 21407241

14. Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, et al. (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19: 739–746. doi: 10.1038/nm.3179 23624599

15. Campanelli AP, Roselino AM, Cavassani KA, Pereira MS, Mortara RA, et al. (2006) CD4+CD25+ T cells in skin lesions of patients with cutaneous leishmaniasis exhibit phenotypic and functional characteristics of natural regulatory T cells. J Infect Dis 193: 1313–1322. 16586370

16. 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. 12466842

17. Couper KN, Blount DG, Wilson MS, Hafalla JC, Belkaid Y, et al. (2008) IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection. PLoS Pathog 4: e1000004. doi: 10.1371/journal.ppat.1000004 18401464

18. Cook PC, Aynsley SA, Turner JD, Jenkins GR, Van Rooijen N, et al. (2011) Multiple helminth infection of the skin causes lymphocyte hypo-responsiveness mediated by Th2 conditioning of dermal myeloid cells. PLoS Pathog 7: e1001323. doi: 10.1371/journal.ppat.1001323 21445234

19. Jenkins SJ, Hewitson JP, Jenkins GR, Mountford AP (2005) Modulation of the host's immune response by schistosome larvae. Parasite Immunol 27: 385–393. 16179032

20. Mountford AP, Trottein F (2004) Schistosomes in the skin: a balance between immune priming and regulation. Trends Parasitol 20: 221–226. 15105022

21. Dorsey CH, Cousin CE, Lewis FA, Stirewalt MA (2002) Ultrastructure of the Schistosoma mansoni cercaria. Micron 33: 279–323. 11742750

22. Jenkins SJ, Hewitson JP, Ferret-Bernard S, Mountford AP (2005) Schistosome larvae stimulate macrophage cytokine production through TLR4-dependent and-independent pathways. Int Immunol 17: 1409–1418. 16186163

23. Jenkins SJ, Mountford AP (2005) Dendritic cells activated with products released by schistosome larvae drive Th2-type immune responses, which can be inhibited by manipulation of CD40 costimulation. Infect Immun 73: 395–402. 15618177

24. Bourke CD, Prendergast CT, Sanin DE, Oulton TE, Hall RJ, et al. (2015) Epidermal keratinocytes initiate wound healing and pro-inflammatory immune responses following percutaneous schistosome infection. Int J Parasitol.

25. Sanin DE, Mountford AP (2015) Sm16, a major component of Schistosoma mansoni cercarial excretory/secretory products, prevents macrophage classical activation and delays antigen processing. Parasit Vectors 8: 1. 25561160

26. Turner JD, Meurs L, Dool P, Bourke CD, Mbow M, et al. (2013) Schistosome infection is associated with enhanced whole-blood IL-10 secretion in response to cercarial excretory/secretory products. Parasite Immunol 35: 147–156. doi: 10.1111/pim.12028 23398537

27. Redpath SA, Fonseca NM, Perona-Wright G (2014) Protection and pathology during parasite infection: IL-10 strikes the balance. Parasite Immunol 36: 233–252. doi: 10.1111/pim.12113 24666543

28. 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. doi: 10.1371/journal.ppat.1002171 21829367

29. Mentink-Kane MM, Cheever AW, Wilson MS, Madala SK, Beers LM, et al. (2011) Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Ralpha2. Gastroenterology 141: 2200–2209. doi: 10.1053/j.gastro.2011.08.008 21864478

30. Hesse M, Piccirillo CA, Belkaid Y, Prufer J, Mentink-Kane M, et al. (2004) The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J Immunol 172: 3157–3166. 14978122

31. Wynn TA, Cheever AW, Williams ME, Hieny S, Caspar P, et al. (1998) IL-10 regulates liver pathology in acute murine Schistosomiasis mansoni but is not required for immune down-modulation of chronic disease. J Immunol 160: 4473–4480. 9574553

32. Scott JT, Diakhate M, Vereecken K, Fall A, Diop M, et al. (2003) Human water contacts patterns in Schistosoma mansoni epidemic foci in northern Senegal change according to age, sex and place of residence, but are not related to intensity of infection. Trop Med Int Health 8: 100–108. 12581433

33. Prendergast CT, Sanin DE, Cook PC, Mountford AP (2015) CD4+ T cell hypo-responsiveness after repeated exposure to Schistosoma mansoni larvae is dependent upon interleukin-10. Infect Immun.

34. Kamanaka M, Kim ST, Wan YY, Sutterwala FS, Lara-Tejero M, et al. (2006) Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25: 941–952. 17137799

35. Saraiva M, O'Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10: 170–181. doi: 10.1038/nri2711 20154735

36. Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, et al. (2012) Compartmentalized control of skin immunity by resident commensals. Science 337: 1115–1119. doi: 10.1126/science.1225152 22837383

37. Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180: 5771–5777. 18424693

38. Kullberg MC, Rothfuchs AG, Jankovic D, Caspar P, Wynn TA, et al. (2001) Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infect Immun 69: 4232–4241. 11401959

39. Kane MM, Mosser DM (2001) The role of IL-10 in promoting disease progression in leishmaniasis. J Immunol 166: 1141–1147. 11145695

40. Sadler CH, Rutitzky LI, Stadecker MJ, Wilson RA (2003) IL-10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoni. Eur J Immunol 33: 880–888. 12672053

41. Hogg KG, Kumkate S, Mountford AP (2003) IL-10 regulates early IL-12-mediated immune responses induced by the radiation-attenuated schistosome vaccine. Int Immunol 15: 1451–1459. 14645154

42. Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM, et al. (2009) Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31: 209–219. doi: 10.1016/j.immuni.2009.05.012 19646904

43. Shoemaker J, Saraiva M, O'Garra A (2006) GATA-3 directly remodels the IL-10 locus independently of IL-4 in CD4+ T cells. J Immunol 176: 3470–3479. 16517715

44. Chang HD, Helbig C, Tykocinski L, Kreher S, Koeck J, et al. (2007) Expression of IL-10 in Th memory lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3. Eur J Immunol 37: 807–817. 17304625

45. Xu J, Yang Y, Qiu G, Lal G, Wu Z, et al. (2009) c-Maf regulates IL-10 expression during Th17 polarization. J Immunol 182: 6226–6236. doi: 10.4049/jimmunol.0900123 19414776

46. Anderson CF, Oukka M, Kuchroo VJ, Sacks D (2007) CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med 204: 285–297. 17283207

47. Joss A, Akdis M, Faith A, Blaser K, Akdis CA (2000) IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol 30: 1683–1690. 10898505

48. Scheer S, Gross S, Mouahid G, Mone H, Lamers MC (2014) A novel tool to identify the relative contribution of lymphoid cell types that contribute to IL-10 production during the infection with Schistosoma mansoni: The TIGER index. J Immunol Methods.

49. Hoffmann KF, Cheever AW, Wynn TA (2000) IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J Immunol 164: 6406–6416. 10843696

50. Satoguina J, Mempel M, Larbi J, Badusche M, Loliger C, et al. (2002) Antigen-specific T regulatory-1 cells are associated with immunosuppression in a chronic helminth infection (onchocerciasis). Microbes Infect 4: 1291–1300. 12443893

51. McKee AS, Pearce EJ (2004) CD25+CD4+ cells contribute to Th2 polarization during helminth infection by suppressing Th1 response development. J Immunol 173: 1224–1231. 15240714

52. Belkaid Y (2008) Role of Foxp3-positive regulatory T cells during infection. Eur J Immunol 38: 918–921. doi: 10.1002/eji.200738120 18395860

53. Kassiotis G, Gray D, Kiafard Z, Zwirner J, Stockinger B (2006) Functional specialization of memory Th cells revealed by expression of integrin CD49b. J Immunol 177: 968–975. 16818752

54. Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, et al. (2012) Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 209: 1723–1742, S1721. 22966001

55. Coomes SM, Pelly VS, Wilson MS (2013) Plasticity within the alphabeta(+)CD4(+) T-cell lineage: when, how and what for? Open Biol 3: 120157. doi: 10.1098/rsob.120157 23345540

56. Kim BS, Kim IK, Park YJ, Kim YS, Kim YJ, et al. (2010) Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma. Proc Natl Acad Sci U S A 107: 8742–8747. doi: 10.1073/pnas.0911756107 20421479

57. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, et al. (2003) Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol 171: 3262–3269. 12960356

58. Turner DL, Farber DL (2014) Mucosal resident memory CD4 T cells in protection and immunopathology. Front Immunol 5: 331. doi: 10.3389/fimmu.2014.00331 25071787

59. Turner DL, Bickham KL, Thome JJ, Kim CY, D'Ovidio F, et al. (2014) Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal Immunol 7: 501–510. doi: 10.1038/mi.2013.67 24064670

60. Bos JD, Hagenaars C, Das PK, Krieg SR, Voorn WJ, et al. (1989) Predominance of "memory" T cells (CD4+, CDw29+) over "naive" T cells (CD4+, CD45R+) in both normal and diseased human skin. Arch Dermatol Res 281: 24–30. 2525009

61. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, et al. (2006) The vast majority of CLA+ T cells are resident in normal skin. J Immunol 176: 4431–4439. 16547281

62. Carbone FR, Mackay LK, Heath WR, Gebhardt T (2013) Distinct resident and recirculating memory T cell subsets in non-lymphoid tissues. Curr Opin Immunol 25: 329–333. doi: 10.1016/j.coi.2013.05.007 23746791

63. Thawer SG, Horsnell WG, Darby M, Hoving JC, Dewals B, et al. (2014) Lung-resident CD4(+) T cells are sufficient for IL-4Ralpha-dependent recall immunity to Nippostrongylus brasiliensis infection. Mucosal Immunol 7: 239–248. doi: 10.1038/mi.2013.40 23778354

64. Ziegler T, Rausch S, Steinfelder S, Klotz C, Hepworth MR, et al. (2015) A Novel Regulatory Macrophage Induced by a Helminth Molecule Instructs IL-10 in CD4+ T Cells and Protects against Mucosal Inflammation. J Immunol.

65. Staples KJ, Smallie T, Williams LM, Foey A, Burke B, et al. (2007) IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3. J Immunol 178: 4779–4785. 17404258

66. Mueller SN (2014) Skin DCs cluster for efficient T cell activation. Nat Immunol 15: 1004–1005. doi: 10.1038/ni.3012 25329181

67. Macleod BL, Bedoui S, Hor JL, Mueller SN, Russell TA, et al. (2014) Distinct APC subtypes drive spatially segregated CD4+ and CD8+ T-cell effector activity during skin infection with HSV-1. PLoS Pathog 10: e1004303. doi: 10.1371/journal.ppat.1004303 25121482

68. Gabrysova L, Howes A, Saraiva M, O'Garra A (2014) The regulation of IL-10 expression. Curr Top Microbiol Immunol 380: 157–190. doi: 10.1007/978-3-662-43492-5_8 25004818

69. Anderson CF, Stumhofer JS, Hunter CA, Sacks D (2009) IL-27 regulates IL-10 and IL-17 from CD4+ cells in nonhealing Leishmania major infection. J Immunol 183: 4619–4627. doi: 10.4049/jimmunol.0804024 19748991

70. Bollrath J, Powrie FM (2013) Controlling the frontier: regulatory T-cells and intestinal homeostasis. Semin Immunol 25: 352–357. doi: 10.1016/j.smim.2013.09.002 24184013

71. Nakamizo S, Egawa G, Honda T, Nakajima S, Belkaid Y, et al. (2014) Commensal bacteria and cutaneous immunity. Semin Immunopathol.

72. Shen W, Li W, Hixon JA, Bouladoux N, Belkaid Y, et al. (2014) Adaptive immunity to murine skin commensals. Proc Natl Acad Sci U S A 111: E2977–2986. doi: 10.1073/pnas.1401820111 25002505

73. Okwuosa VN, Osuala FO (1993) Toxicity of washing soaps to Schistosoma mansoni cercariae and effects of sublethal concentrations on infectivity in mice. Appl Parasitol 34: 69–75. 8508221

74. de Silva NR, Brooker S, Hotez PJ, Montresor A, Engels D, et al. (2003) Soil-transmitted helminth infections: updating the global picture. Trends Parasitol 19: 547–551. 14642761

75. Kolarova L, Horak P, Skirnisson K, Mareckova H, Doenhoff M (2013) Cercarial dermatitis, a neglected allergic disease. Clin Rev Allergy Immunol 45: 63–74. doi: 10.1007/s12016-012-8334-y 22915284

76. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75: 263–274. 8402911

77. Mountford AP, Hogg KG, Coulson PS, Brombacher F (2001) Signaling via interleukin-4 receptor alpha chain is required for successful vaccination against schistosomiasis in BALB/c mice. Infect Immun 69: 228–236. 11119510

78. Mendez S, Reckling SK, Piccirillo CA, Sacks D, Belkaid Y (2004) Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity. J Exp Med 200: 201–210. 15263027

79. Mountford AP, Harrop R, Wilson RA (1995) Antigens derived from lung-stage larvae of Schistosoma mansoni are efficient stimulators of proliferation and gamma interferon secretion by lymphocytes from mice vaccinated with attenuated larvae. Infect Immun 63: 1980–1986. 7729911

80. Hogg KG, Kumkate S, Anderson S, Mountford AP (2003) Interleukin-12 p40 secretion by cutaneous CD11c+ and F4/80+ cells is a major feature of the innate immune response in mice that develop Th1-mediated protective immunity to Schistosoma mansoni. Infect Immun 71: 3563–3571. 12761141