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Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells

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Abstract

CD4 T-helper (Th) cells secret a variety of inflammatory cytokines and play critical roles in host defense against invading foreign pathogens. On the other hand, uncontrolled inflammatory responses mediated by Th cells may result in tissue damage and inflammatory disorders including autoimmune and allergic diseases. Thus, the induction of anti-inflammatory cytokine expression becomes an important “brake” to repress and/or terminate aberrant and/or unnecessary immune responses. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines to limit inflammatory Th cells and immunopathology and to maintain tissue homeostasis. Many studies have indicated that Th cells can be a major source of IL-10 under specific conditions both in mouse and human and that extracellular signals and cell intrinsic molecular switches are required to turn on and off Il10 expression in different Th cells. In this review, we will highlight the recent findings that have enhanced our understanding on the mechanisms of IL-10 induction in distinct Th-cell subsets, including Th1, Th2, and Th17 cells, as well as the importance of these IL-10-producing anti-inflammatory Th cells in immunity and inflammation.

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References

  1. Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations. Annu Rev Immunol 28:445–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Crotty S (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29:621–663

    Article  CAS  PubMed  Google Scholar 

  3. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fang D, Zhu J (2017) Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets. J Exp Med 214(7):1861–1876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. O’Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327(5969):1098–1102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Fiorentino DF (1989) Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170(6):2081–2095

    Article  CAS  PubMed  Google Scholar 

  7. Ng TH, Britton GJ, Hill EV, Verhagen J, Burton BR, Wraith DC (2013) Regulation of adaptive immunity; the role of interleukin-10. Front Immunol 4:129

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hawrylowicz CM, O’Garra A (2005) Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 5(4):271–283

    Article  CAS  PubMed  Google Scholar 

  9. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    Article  CAS  PubMed  Google Scholar 

  10. Maloy KJ, Powrie F (2001) Regulatory T cells in the control of immune pathology. Nat Immunol 2(9):816–822

    Article  CAS  PubMed  Google Scholar 

  11. Maynard CL, Harrington LE, Janowski KM, Oliver JR, Zindl CL, Rudensky AY et al (2007) Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10. Nat Immunol 8(9):931–941

    Article  CAS  PubMed  Google Scholar 

  12. Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A et al (2004) IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol 172(10):5986–5993

    Article  CAS  PubMed  Google Scholar 

  13. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    Article  CAS  PubMed  Google Scholar 

  14. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X et al (2008) Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28(4):546–558

    Article  CAS  PubMed  Google Scholar 

  15. Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE et al (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389(6652):737–742

    Article  CAS  PubMed  Google Scholar 

  16. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28–50

    Article  CAS  PubMed  Google Scholar 

  17. Gerosa F (1996) Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-gamma and interleukin-10. J Exp Med 183(6):2559–2569

    Article  CAS  PubMed  Google Scholar 

  18. Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S (1993) Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 150(2):353–360

    PubMed  Google Scholar 

  19. Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10(3):170–181

    Article  CAS  PubMed  Google Scholar 

  20. Adachi M, Oda N, Kokubu F, Minoguchi K (1999) IL-10 induces a Th2 cell tolerance in allergic asthma. Int Arch Allergy Immunol 118(2–4):391–394

    Article  CAS  PubMed  Google Scholar 

  21. Sanin DE, Prendergast CT, Bourke CD, Mountford AP (2015) 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):e1004841

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Coomes SM, Kannan Y, Pelly VS, Entwistle LJ, Guidi R, Perez-Lloret J et al (2017) CD4(+) Th2 cells are directly regulated by IL-10 during allergic airway inflammation. Mucosal Immunol 10(1):150–161

    Article  CAS  PubMed  Google Scholar 

  23. Chatterjee P, Chiasson VL, Bounds KR, Mitchell BM (2014) Regulation of the anti-inflammatory cytokines interleukin-4 and interleukin-10 during pregnancy. Front Immunol 5:253

    PubMed  PubMed Central  Google Scholar 

  24. Jagannathan P, Eccles-James I, Bowen K, Nankya F, Auma A, Wamala S et al (2014) IFNgamma/IL-10 co-producing cells dominate the CD4 response to malaria in highly exposed children. PLoS Pathog 10(1):e1003864

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Portugal S, Moebius J, Skinner J, Doumbo S, Doumtabe D, Kone Y et al (2014) Exposure-dependent control of malaria-induced inflammation in children. PLoS Pathog 10(4):e1004079

    Article  PubMed  PubMed Central  Google Scholar 

  26. Walther M, Jeffries D, Finney OC, Njie M, Ebonyi A, Deininger S 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(4):e1000364

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kumar R, Ng S, Engwerda C (2019) The role of IL-10 in malaria: a double edged sword. Front Immunol 10:229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Costa DL, Cardoso TM, Queiroz A, Milanezi CM, Bacellar O, Carvalho EM et al (2015) Tr-1-like CD4+CD25CD127/lowFOXP3 cells are the main source of interleukin 10 in patients with cutaneous leishmaniasis due to Leishmania braziliensis. J Infect Dis 211(5):708–718

    Article  CAS  PubMed  Google Scholar 

  29. Owens BM, Beattie L, Moore JW, Brown N, Mann JL, Dalton JE et al (2012) IL-10-producing Th1 cells and disease progression are regulated by distinct CD11c(+) cell populations during visceral leishmaniasis. PLoS Pathog 8(7):e1002827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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(2):285–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gerosa F, Nisii C, Righetti S, Micciolo R, Marchesini M, Cazzadori A et al (1999) CD4(+) T cell clones producing both interferon-gamma and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin Immunol 92(3):224–234

    Article  CAS  PubMed  Google Scholar 

  32. Chowdhury IH, Ahmed AM, Choudhuri S, Sen A, Hazra A, Pal NK et al (2014) Alteration of serum inflammatory cytokines in active pulmonary tuberculosis following anti-tuberculosis drug therapy. Mol Immunol 62(1):159–168

    Article  CAS  PubMed  Google Scholar 

  33. Harling K, Adankwah E, Guler A, Afum-Adjei Awuah A, Adu-Amoah L, Mayatepek E et al (2019) Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients. Cell Mol Immunol 16(3):275–287

    Article  CAS  PubMed  Google Scholar 

  34. Kumar NP, Moideen K, Banurekha VV, Nair D, Sridhar R, Nutman TB et al (2015) IL-27 and TGFbeta mediated expansion of Th1 and adaptive regulatory T cells expressing IL-10 correlates with bacterial burden and disease severity in pulmonary tuberculosis. Immun Inflamm Dis 3(3):289–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Moreira-Teixeira L, Redford PS, Stavropoulos E, Ghilardi N, Maynard CL, Weaver CT et al (2017) T cell-derived IL-10 impairs host resistance to Mycobacterium tuberculosis infection. J Immunol 199(2):613–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Weiss KA, Christiaansen AF, Fulton RB, Meyerholz DK, Varga SM (2011) Multiple CD4+ T cell subsets produce immunomodulatory IL-10 during respiratory syncytial virus infection. J Immunol 187(6):3145–3154

    Article  CAS  PubMed  Google Scholar 

  37. Jankovic D, Kullberg MC, Feng CG, Goldszmid RS, Collazo CM, Wilson M et al (2007) Conventional T-bet(+)Foxp3(−) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med 204(2):273–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Roers A, Siewe L, Strittmatter E, Deckert M, Schluter D, Stenzel W et al (2004) T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J Exp Med 200(10):1289–1297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu X, Tian J, Wang S (2018) Insight into non-pathogenic Th17 cells in autoimmune diseases. Front Immunol 9:1112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hu D, Notarbartolo S, Croonenborghs T, Patel B, Cialic R, Yang TH et al (2017) Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis. Nat Commun 8(1):1600

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Cao Y, Goods BA, Raddassi K, Nepom GT, Kwok WW, Love JC et al (2015) Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci Transl Med 7(287):287ra74

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Hong Qi YC, Inomata T, Amouzegar A, Dana R (2017) IL-10-producing Th17 cells: a potentially regulatory cell population in dry eye disease. J Immunol Immunother 2(1:5)

  43. Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M et al (2012) Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature 484(7395):514–518

    Article  CAS  PubMed  Google Scholar 

  44. Kulcsar KA, Baxter VK, Greene IP, Griffin DE (2014) Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis. Proc Natl Acad Sci USA 111(45):16053–16058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kulcsar KA, Griffin DE (2016) T cell-derived interleukin-10 is an important regulator of the Th17 response during lethal alphavirus encephalomyelitis. J Neuroimmunol 295–296:60–67

    Article  PubMed  CAS  Google Scholar 

  46. Im SH, Hueber A, Monticelli S, Kang KH, Rao A (2004) Chromatin-level regulation of the IL10 gene in T cells. J Biol Chem 279(45):46818–46825

    Article  CAS  PubMed  Google Scholar 

  47. Jones EA, Flavell RA (2005) Distal enhancer elements transcribe intergenic RNA in the IL-10 family gene cluster. J Immunol 175(11):7437–7446

    Article  CAS  PubMed  Google Scholar 

  48. Kang KH, Im SH (2005) Differential regulation of the IL-10 gene in Th1 and Th2 T cells. Ann N Y Acad Sci 1050:97–107

    Article  CAS  PubMed  Google Scholar 

  49. Wang ZY, Sato H, Kusam S, Sehra S, Toney LM, Dent AL (2005) Regulation of IL-10 gene expression in Th2 cells by Jun proteins. J Immunol 174(4):2098–2105

    Article  CAS  PubMed  Google Scholar 

  50. Koh B, Hufford MM, Sun X, Kaplan MH (2017) Etv5 regulates IL-10 production in Th cells. J Immunol 198(5):2165–2171

    Article  CAS  PubMed  Google Scholar 

  51. 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(6):3470–3479

    Article  CAS  PubMed  Google Scholar 

  52. Chang HD, Helbig C, Tykocinski L, Kreher S, Koeck J, Niesner U 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(3):807–817

    Article  CAS  PubMed  Google Scholar 

  53. Lee CG, Kang KH, So JS, Kwon HK, Son JS, Song MK et al (2009) A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells. Mol Immunol 46(4):613–621

    Article  CAS  PubMed  Google Scholar 

  54. Cao S, Liu J, Chesi M, Bergsagel PL, Ho IC, Donnelly RP et al (2002) Differential regulation of IL-12 and IL-10 gene expression in macrophages by the basic leucine zipper transcription factor c-Maf fibrosarcoma. J Immunol 169(10):5715–5725

    Article  CAS  PubMed  Google Scholar 

  55. Cao S, Liu J, Song L, Ma X (2005) The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J Immunol 174(6):3484–3492

    Article  CAS  PubMed  Google Scholar 

  56. Xu M, Pokrovskii M, Ding Y, Yi R, Au C, Harrison OJ et al (2018) c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554(7692):373–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Neumann C, Blume J, Roy U, Teh PP, Vasanthakumar A, Beller A et al (2019) c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis. Nat Immunol 20(4):471–481

    Article  CAS  PubMed  Google Scholar 

  58. Neumann C, Heinrich F, Neumann K, Junghans V, Mashreghi MF, Ahlers J et al (2014) Role of Blimp-1 in programing Th effector cells into IL-10 producers. J Exp Med 211(9):1807–1819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lin CC, Bradstreet TR, Schwarzkopf EA, Sim J, Carrero JA, Chou C et al (2014) Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation. Nat Commun 5:3551

    Article  PubMed  CAS  Google Scholar 

  60. Huynh JP, Lin CC, Kimmey JM, Jarjour NN, Schwarzkopf EA, Bradstreet TR et al (2018) Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection. J Exp Med 215(7):1823–1838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kitani A, Fuss I, Nakamura K, Kumaki F, Usui T, Strober W (2003) Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. J Exp Med 198(8):1179–1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Huss DJ, Winger RC, Cox GM, Guerau-de-Arellano M, Yang Y, Racke MK et al (2011) TGF-beta signaling via Smad4 drives IL-10 production in effector Th1 cells and reduces T-cell trafficking in EAE. Eur J Immunol 41(10):2987–2996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li P, Spolski R, Liao W, Wang L, Murphy TL, Murphy KM et al (2012) BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature 490(7421):543–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tanaka S, Jiang Y, Martinez GJ, Tanaka K, Yan X, Kurosaki T et al (2018) Trim33 mediates the proinflammatory function of Th17 cells. J Exp Med 215(7):1853–1868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Meyer Zu Horste G, Wu C, Wang C, Cong L, Pawlak M, Lee Y et al (2016) RBPJ controls development of pathogenic Th17 cells by regulating IL-23 receptor expression. Cell Rep 16(2):392–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J et al (2002) IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16(6):779–790

    Article  CAS  PubMed  Google Scholar 

  67. Hamano S, Himeno K, Miyazaki Y, Ishii K, Yamanaka A, Takeda A et al (2003) WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity 19(5):657–667

    Article  CAS  PubMed  Google Scholar 

  68. Villarino A, Hibbert L, Lieberman L, Wilson E, Mak T, Yoshida H et al (2003) The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19(5):645–655

    Article  CAS  PubMed  Google Scholar 

  69. Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R et al (2009) Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol. 183(2):797–801

    Article  CAS  PubMed  Google Scholar 

  70. Aschenbrenner D, Foglierini M, Jarrossay D, Hu D, Weiner HL, Kuchroo VK et al (2018) An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells. Nat Immunol 19(10):1126–1136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D et al (2010) The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 11(9):854–861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Spolski R, Kim HP, Zhu W, Levy DE, Leonard WJ (2009) IL-21 mediates suppressive effects via its induction of IL-10. J Immunol 182(5):2859–2867

    Article  CAS  PubMed  Google Scholar 

  73. Löhning M, Hutloff A, Kallinich T, Mages HW, Bonhagen K, Radbruch A et al (2003) Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J Exp Med 197(2):181–193

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA et al (2007) Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 8(12):1363–1371

    Article  CAS  PubMed  Google Scholar 

  75. Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA et al (2007) A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 8(12):1380–1389

    Article  CAS  PubMed  Google Scholar 

  76. Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H, Yu S et al (2007) Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol 8(12):1372–1379

    Article  CAS  PubMed  Google Scholar 

  77. Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM, O’Garra A (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(2):209–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hill EV, Ng TH, Burton BR, Oakley CM, Malik K, Wraith DC (2015) Glycogen synthase kinase-3 controls IL-10 expression in CD4(+) effector T-cell subsets through epigenetic modification of the IL-10 promoter. Eur J Immunol 45(4):1103–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Britton GJ, Mitchell RE, Burton BR, Wraith DC (2017) Protein kinase C theta is required for efficient induction of IL-10-secreting T cells. PLoS One 12(2):e0171547

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Gabrysova L, Howes A, Saraiva M, O’Garra A (2014) The regulation of IL-10 expression. Curr Top Microbiol Immunol 380:157–190

    CAS  PubMed  Google Scholar 

  81. Zheng WP, Flavell RA (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89(4):587–596

    Article  CAS  PubMed  Google Scholar 

  82. Mitchell RE, Hassan M, Burton BR, Britton G, Hill EV, Verhagen J et al (2017) IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation. Sci Rep 7(1):11315

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Newcomb DC, Boswell MG, Huckabee MM, Goleniewska K, Dulek DE, Reiss S et al (2012) IL-13 regulates Th17 secretion of IL-17A in an IL-10-dependent manner. J Immunol 188(3):1027–1035

    Article  CAS  PubMed  Google Scholar 

  84. Caucheteux SM, Hu-Li J, Guo L, Bhattacharyya N, Crank M, Collins MT et al (2016) IL-1beta enhances inflammatory TH2 differentiation. J Allergy Clin Immunol 138(3):898–901.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Motomura Y, Kitamura H, Hijikata A, Matsunaga Y, Matsumoto K, Inoue H et al (2011) The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nat Immunol 12(5):450–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Umetsu SE, Winandy S (2009) Ikaros is a regulator of Il10 expression in CD4+ T cells. J Immunol 183(9):5518–5525

    Article  CAS  PubMed  Google Scholar 

  87. van Scott MR, Justice JP, Bradfield JF, Enright E, Sigounas A, Sur S (2000) IL-10 reduces Th2 cytokine production and eosinophilia but augments airway reactivity in allergic mice. Am J Physiol Lung Cell Mol Physiol 278(4):L667–L674

    Article  PubMed  Google Scholar 

  88. Laouini D, Alenius H, Bryce P, Oettgen H, Tsitsikov E, Geha RS (2003) IL-10 is critical for Th2 responses in a murine model of allergic dermatitis. J Clin Investig 112(7):1058–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cope A, Le Friec G, Cardone J, Kemper C (2011) The Th1 life cycle: molecular control of IFN-gamma to IL-10 switching. Trends Immunol 32(6):278–286

    Article  CAS  PubMed  Google Scholar 

  90. O’Garra A, Vieira P (2007) T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol 7(6):425–428

    Article  PubMed  CAS  Google Scholar 

  91. Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29:71–109

    Article  CAS  PubMed  Google Scholar 

  92. Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R et al (1996) In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha. J Immunol 157(2):798–805

    CAS  PubMed  Google Scholar 

  93. Freitas do Rosario AP, Lamb T, Spence P, Stephens R, Lang A, Roers A et al (2012) IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J Immunol 188(3):1178–1190

    Article  CAS  PubMed  Google Scholar 

  94. Villegas-Mendez A, Shaw TN, Inkson CA, Strangward P, de Souza JB, Couper KN (2016) Parasite-specific CD4+ IFN-gamma+ IL-10+ T cells distribute within both lymphoid and nonlymphoid compartments and are controlled systemically by interleukin-27 and ICOS during blood-stage malaria infection. Infect Immun 84(1):34–46

    Article  CAS  PubMed  Google Scholar 

  95. Jankovic D, Kullberg MC, Hieny S, Caspar P, Collazo CM, Sher A (2002) In the absence of IL-12, CD4(+) T cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10(−/−) setting. Immunity 16(3):429–439

    Article  CAS  PubMed  Google Scholar 

  96. Huss DJ, Winger RC, Peng H, Yang Y, Racke MK, Lovett-Racke AE (2010) TGF-beta enhances effector Th1 cell activation but promotes self-regulation via IL-10. J Immunol 184(10):5628–5636

    Article  CAS  PubMed  Google Scholar 

  97. Salehi S, Bankoti R, Benevides L, Willen J, Couse M, Silva JS et al (2012) B lymphocyte-induced maturation protein-1 contributes to intestinal mucosa homeostasis by limiting the number of IL-17-producing CD4+ T cells. J Immunol 189(12):5682–5693

    Article  CAS  PubMed  Google Scholar 

  98. Blom L, Poulsen LK (2012) IL-1 family members IL-18 and IL-33 upregulate the inflammatory potential of differentiated human Th1 and Th2 cultures. J Immunol 189(9):4331–4337

    Article  CAS  PubMed  Google Scholar 

  99. Yu F, Sharma S, Jankovic D, Gurram RK, Su P, Hu G et al (2018) The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination. J Exp Med 215(7):1813–1821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gabrysova L, Alvarez-Martinez M, Luisier R, Cox LS, Sodenkamp J, Hosking C et al (2018) c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells. Nat Immunol 19(5):497–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Evans HG, Roostalu U, Walter GJ, Gullick NJ, Frederiksen KS, Roberts CA et al (2014) TNF-alpha blockade induces IL-10 expression in human CD4+ T cells. Nat Commun 5:3199

    Article  PubMed  CAS  Google Scholar 

  102. Parish IA, Marshall HD, Staron MM, Lang PA, Brustle A, Chen JH et al (2014) Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. J Clin Investig 124(8):3455–3468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Xin G, Zander R, Schauder DM, Chen Y, Weinstein JS, Drobyski WR et al (2018) Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection. Nat Commun 9(1):5037

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Iwasaki Y, Fujio K, Okamura T, Yanai A, Sumitomo S, Shoda H et al (2013) Egr-2 transcription factor is required for Blimp-1-mediated IL-10 production in IL-27-stimulated CD4+ T cells. Eur J Immunol 43(4):1063–1073

    Article  CAS  PubMed  Google Scholar 

  105. Rutz S, Janke M, Kassner N, Hohnstein T, Krueger M, Scheffold A (2008) Notch regulates IL-10 production by T helper 1 cells. Proc Natl Acad Sci USA 105(9):3497–3502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cardone J, Le Friec G, Vantourout P, Roberts A, Fuchs A, Jackson I et al (2010) Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat Immunol 11(9):862–871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA (2012) The TIGIT/CD226 axis regulates human T cell function. J Immunol 188(8):3869–3875

    Article  CAS  PubMed  Google Scholar 

  108. Kemp KL, Levin SD, Stein PL (2010) Lck regulates IL-10 expression in memory-like Th1 cells. Eur J Immunol 40(11):3210–3219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Perucha E, Melchiotti R, Bibby JA, Wu W, Frederiksen KS, Roberts CA et al (2019) The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nat Commun 10(1):498

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Dryden GW (2009) Overview of stem cell therapy for Crohn’s disease. Expert Opin Biol Ther 9(7):841–847

    Article  CAS  PubMed  Google Scholar 

  111. Selleri S, Dieng MM, Nicoletti S, Louis I, Beausejour C, Le Deist F et al (2013) Cord-blood-derived mesenchymal stromal cells downmodulate CD4+ T-cell activation by inducing IL-10-producing Th1 cells. Stem Cells Dev 22(7):1063–1075

    Article  CAS  PubMed  Google Scholar 

  112. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517

    Article  CAS  PubMed  Google Scholar 

  113. Huber S, Gagliani N, Esplugues E, O’Connor W Jr, Huber FJ, Chaudhry A et al (2011) Th17 cells express interleukin-10 receptor and are controlled by Foxp3(−) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34(4):554–565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T et al (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8(12):1390–1397

    Article  CAS  PubMed  Google Scholar 

  115. Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A et al (2012) Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13(10):991–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Xu J, Yang Y, Qiu G, Lal G, Wu Z, Levy DE et al (2009) c-Maf regulates IL-10 expression during Th17 polarization. J Immunol 182(10):6226–6236

    Article  CAS  PubMed  Google Scholar 

  117. Jin JO, Han X, Yu Q (2013) Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation. J Autoimmun 40:28–44

    Article  CAS  PubMed  Google Scholar 

  118. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE et al (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467(7318):967–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD et al (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201(2):233–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Jager A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183(11):7169–7177

    Article  PubMed  CAS  Google Scholar 

  121. Chang KK, Liu LB, Jin LP, Zhang B, Mei J, Li H et al (2017) IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORgammat/Blimp-1 signal to promote the progression of endometriosis. Cell Death Dis 8(3):e2666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhang L, Yuan S, Cheng G, Guo B (2011) Type I IFN promotes IL-10 production from T cells to suppress Th17 cells and Th17-associated autoimmune inflammation. PLoS One 6(12):e28432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Martin-Saavedra FM, Gonzalez-Garcia C, Bravo B, Ballester S (2008) Beta interferon restricts the inflammatory potential of CD4+ cells through the boost of the Th2 phenotype, the inhibition of Th17 response and the prevalence of naturally occurring T regulatory cells. Mol Immunol 45(15):4008–4019

    Article  CAS  PubMed  Google Scholar 

  124. Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P et al (2010) T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 16(4):406–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lin CC, Bradstreet TR, Schwarzkopf EA, Jarjour NN, Chou C, Archambault AS et al (2016) IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation. J Exp Med 213(2):251–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. He W, Dorn DC, Erdjument-Bromage H, Tempst P, Moore MA, Massague J (2006) Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. Cell 125(5):929–941

    Article  CAS  PubMed  Google Scholar 

  127. Xiao S, Yosef N, Yang J, Wang Y, Zhou L, Zhu C et al (2014) Small-molecule RORgammat antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40(4):477–489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kurokawa J, Arai S, Nakashima K, Nagano H, Nishijima A, Miyata K et al (2010) Macrophage-derived AIM is endocytosed into adipocytes and decreases lipid droplets via inhibition of fatty acid synthase activity. Cell Metab 11(6):479–492

    Article  CAS  PubMed  Google Scholar 

  129. Wang C, Yosef N, Gaublomme J, Wu C, Lee Y, Clish CB et al (2015) CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163(6):1413–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Longhi MS, Vuerich M, Kalbasi A, Kenison JE, Yeste A, Csizmadia E et al (2017) Bilirubin suppresses Th17 immunity in colitis by upregulating CD39. JCI Insight 2(9):92791

    Article  PubMed  Google Scholar 

  131. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N Engl J Med 339(5):285–291

    Article  CAS  PubMed  Google Scholar 

  132. Yates MA, Li Y, Chlebeck PJ, Offner H (2010) GPR30, but not estrogen receptor-alpha, is crucial in the treatment of experimental autoimmune encephalomyelitis by oral ethinyl estradiol. BMC Immunol 11:20

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Brunsing RL, Prossnitz ER (2011) Induction of interleukin-10 in the T helper type 17 effector population by the G protein coupled estrogen receptor (GPER) agonist G-1. Immunology 134(1):93–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Mann EH, Gabrysova L, Pfeffer PE, O’Garra A, Hawrylowicz CM (2019) High-dose IL-2 skews a glucocorticoid-driven IL-17(+)IL-10(+) memory CD4(+) T cell response towards a single IL-10-producing phenotype. J Immunol 202(3):684–693

    Article  CAS  PubMed  Google Scholar 

  135. Volchenkov R, Nygaard V, Sener Z, Skalhegg BS (2017) Th17 polarization under hypoxia results in increased IL-10 production in a pathogen-independent manner. Front Immunol 8:698

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y et al (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496(7446):513–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM et al (2011) Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34(4):566–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Revu S, Wu J, Henkel M, Rittenhouse N, Menk A, Delgoffe GM et al (2018) IL-23 and IL-1beta drive human Th17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation. Cell Rep 22(10):2642–2653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Artis D, Spits H (2015) The biology of innate lymphoid cells. Nature 517(7534):293–301

    Article  CAS  PubMed  Google Scholar 

  140. Lee SH, Kim KS, Fodil-Cornu N, Vidal SM, Biron CA (2009) Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection. J Exp Med 206(10):2235–2251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK et al (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464(7293):1367–1370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Gury-BenAri M, Thaiss CA, Serafini N, Winter DR, Giladi A, Lara-Astiaso D et al (2016) The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell 166(5):1231–1246.e13

    Article  CAS  PubMed  Google Scholar 

  143. Wang S, Xia P, Chen Y, Qu Y, Xiong Z, Ye B et al (2017) Regulatory innate lymphoid cells control innate intestinal inflammation. Cell 171(1):201–216.e18

    Article  CAS  PubMed  Google Scholar 

  144. Seehus CR, Kadavallore A, Torre B, Yeckes AR, Wang Y, Tang J et al (2017) Alternative activation generates IL-10 producing type 2 innate lymphoid cells. Nat Commun 8(1):1900

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Brockmann L, Soukou S, Steglich B, Czarnewski P, Zhao L, Wende S et al (2018) Molecular and functional heterogeneity of IL-10-producing CD4(+) T cells. Nat Commun 9(1):5457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Liu M, Zhao X, Ma Y, Zhou Y, Deng M, Ma Y (2018) Transcription factor c-Maf is essential for IL-10 gene expression in B cells. Scand J Immunol 88(3):e12701

    Article  PubMed  CAS  Google Scholar 

  147. Gabrysova L, O’Garra A (2018) Regulating the regulator: Bhlhe40 directly keeps IL-10 in check. J Exp Med 215(7):1767–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sun H, Lu B, Li RQ, Flavell RA, Taneja R (2001) Defective T cell activation and autoimmune disorder in Stra13-deficient mice. Nat Immunol 2(11):1040–1047

    Article  CAS  PubMed  Google Scholar 

  149. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75(2):263–274

    Article  CAS  PubMed  Google Scholar 

  150. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F et al (2009) Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361(21):2033–2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (No. 1-ZIA-AI001169).

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Fang, D., Zhu, J. Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells. Cell. Mol. Life Sci. 77, 289–303 (2020). https://doi.org/10.1007/s00018-019-03277-0

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