Intestinal IFN-γ–producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease

Journal of Allergy and Clinical Immunology

Volumn 142, Issue 5, 2018, Pages 1537-1547.e8

  Alfen, Johanna Sophie ^a   Larghi, Paola ^a,b   Facciotti, Federica ^a   Gagliani, Nicola ^c,d   Bosotti, Roberto ^a   Paroni, Moira ^a   Maglie, Stefano ^a   Gruarin, Paola ^a   Vasco, Chiara Maria ^a   Ranzani, Valeria ^a   Frusteri, Cristina ^e   Iseppon, Andrea ^d   Moro, Monica ^a   Crosti, Maria Cristina ^a   Gatti, Stefano ^e   Pagani, Massimiliano ^a,b   Caprioli, Flavio ^b,e   Abrignani, Sergio ^a,b   Flavell, Richard A ^d   Geginat, Jens ^a  

^a INGM   (Italy)

^b UNIVERSITY OF MILAN   (Italy)

^c UNIVERSITY MEDICAL CENTER HAMBURG EPPENDORF   (Germany)

^d YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e FONDAZIONE IRCCS CA GRANDA OSPEDALE MAGGIORE POLICLINICO   (Italy)

Author keywords

IL 10; IL 23; Inflammatory bowel disease; regulatory T cells

Indexed keywords

CHEMOKINE RECEPTOR CCR5; GAMMA INTERFERON; INTERLEUKIN 1 RECEPTOR TYPE I; INTERLEUKIN 1 RECEPTOR TYPE II; INTERLEUKIN 10; INTERLEUKIN 1BETA; INTERLEUKIN 23; INTERLEUKIN 7 RECEPTOR; MESSENGER RNA; PROGRAMMED DEATH 1 RECEPTOR; STAT3 PROTEIN; CCR5 PROTEIN, HUMAN; CYTOKINE; PDCD1 PROTEIN, HUMAN;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CD4+ T LYMPHOCYTE; CELL ISOLATION; CONTROLLED STUDY; CYTOKINE PRODUCTION; DOWN REGULATION; FEMALE; HUMAN; HUMAN CELL; INFLAMMATORY BOWEL DISEASE; LAMINA PROPRIA; LYMPHOCYTE PROLIFERATION; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; AGED; ANIMAL; C57BL MOUSE; CELL CULTURE; COLON TUMOR; IMMUNOLOGY; INTESTINE MUCOSA; MIDDLE AGED; TRANSGENIC MOUSE; YOUNG ADULT;

ADULT; AGED; ANIMALS; CELLS, CULTURED; COLONIC NEOPLASMS; CYTOKINES; FEMALE; HUMANS; INFLAMMATORY BOWEL DISEASES; INTESTINAL MUCOSA; MALE; MICE, INBRED C57BL; MICE, TRANSGENIC; MIDDLE AGED; PROGRAMMED CELL DEATH 1 RECEPTOR; RECEPTORS, CCR5; T-LYMPHOCYTES, REGULATORY; YOUNG ADULT;

EID: 85042181305     PISSN: 00916749     EISSN: 10976825     Source Type: Journal    
DOI: 10.1016/j.jaci.2017.12.984     Document Type: Article

References (55)

1. Moore, K.W., de Waal Malefyt, R., Coffman, R.L., O'Garra, A., Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19 (2001), 683–765.
2. Sabat, R., Grutz, G., Warszawska, K., Kirsch, S., Witte, E., Wolk, K., et al. Biology of interleukin-10. Cytokine Growth Factor Rev 21 (2010), 331–344.
3. Glocker, E.O., Kotlarz, D., Klein, C., Shah, N., Grimbacher, B., IL-10 and IL-10 receptor defects in humans. Ann N Y Acad Sci 1246 (2011), 102–107.
4. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K., Muller, W., Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75 (1993), 263–274.
5. Sellon, R.K., Tonkonogy, S., Schultz, M., Dieleman, L.A., Grenther, W., Balish, E., et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun 66 (1998), 5224–5231.
6. Roers, A., Siewe, L., Strittmatter, E., Deckert, M., Schluter, D., Stenzel, W., et al. 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 (2004), 1289–1297.
7. Rubtsov, Y.P., Rasmussen, J.P., Chi, E.Y., Fontenot, J., Castelli, L., Ye, X., et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28 (2008), 546–558.
8. Asseman, C., Mauze, S., Leach, M.W., Coffman, R.L., Powrie, F., An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 190 (1999), 995–1004.
9. Uhlig, H.H., Coombes, J., Mottet, C., Izcue, A., Thompson, C., Fanger, A., et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol 177 (2006), 5852–5860.
10. Huber, S., Gagliani, N., Esplugues, E., O'Connor, W. Jr., Huber, F.J., Chaudhry, A., et al. 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 (2011), 554–565.
11. Zigmond, E., Bernshtein, B., Friedlander, G., Walker, C.R., Yona, S., Kim, K.W., et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 40 (2014), 720–733.
12. Groux, H., O'Garra, A., Bigler, M., Rouleau, M., Antonenko, S., de Vries, J.E., et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389 (1997), 737–742.
13. Maynard, C.L., Harrington, L.E., Janowski, K.M., Oliver, J.R., Zindl, C.L., Rudensky, A.Y., et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. Nat Immunol 8 (2007), 931–941.
14. Vieira, P.L., Christensen, J.R., Minaee, S., O'Neill, E.J., Barrat, F.J., Boonstra, A., et al. 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 (2004), 5986–5993.
15. O'Garra, A., Vieira, P.L., Vieira, P., Goldfeld, A.E., IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J Clin Invest 114 (2004), 1372–1378.
16. Akdis, M., Verhagen, J., Taylor, A., Karamloo, F., Karagiannidis, C., Crameri, R., et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 199 (2004), 1567–1575.
17. Chaudhry, A., Samstein, R.M., Treuting, P., Liang, Y., Pils, M.C., Heinrich, J.M., et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34 (2011), 566–578.
18. Barrat, F.J., Cua, D.J., Boonstra, A., Richards, D.F., Crain, C., Savelkoul, H.F., et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 195 (2002), 603–616.
19. Kemper, C., Chan, A.C., Green, J.M., Brett, K.A., Murphy, K.M., Atkinson, J.P., Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421 (2003), 388–392.
20. Levings, M.K., Gregori, S., Tresoldi, E., Cazzaniga, S., Bonini, C., Roncarolo, M.G., Differentiation of TR1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105 (2005), 1162–1169.
21. Allan, S.E., Broady, R., Gregori, S., Himmel, M.E., Locke, N., Roncarolo, M.G., et al. CD4+ T-regulatory cells: toward therapy for human diseases. Immunol Rev 223 (2008), 391–421.
22. Desreumaux, P., Foussat, A., Allez, M., Beaugerie, L., Hebuterne, X., Bouhnik, Y., et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. Gastroenterology 143 (2012), 1207–1217 e1-2.
23. Bacchetta, R., Lucarelli, B., Sartirana, C., Gregori, S., Lupo Stanghellini, M.T., Miqueu, P., et al. Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells. Front Immunol, 5, 2014, 16.
24. Haringer, B., Lozza, L., Steckel, B., Geginat, J., Identification and characterization of IL-10/IFN-gamma-producing effector-like T cells with regulatory function in human blood. J Exp Med 206 (2009), 1009–1017.
25. Facciotti, F., Gagliani, N., Haringer, B., Alfen, J.S., Penatti, A., Maglie, S., et al. IL-10-producing forkhead box protein 3-negative regulatory T cells inhibit B-cell responses and are involved in systemic lupus erythematosus. J Allergy Clin Immunol 137 (2016), 318–321.e5.
26. Gagliani, N., Magnani, C.F., Huber, S., Gianolini, M.E., Pala, M., Licona-Limon, P., et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19 (2013), 739–746.
27. Caprioli, F., Sarra, M., Caruso, R., Stolfi, C., Fina, D., Sica, G., et al. Autocrine regulation of IL-21 production in human T lymphocytes. J Immunol 180 (2008), 1800–1807.
28. Kastirr, I., Maglie, S., Paroni, M., Alfen, J.S., Nizzoli, G., Sugliano, E., et al. IL-21 is a central memory T cell-associated cytokine that inhibits the generation of pathogenic Th1/17 effector cells. J Immunol 193 (2014), 3322–3331.
29. Okamura, T., Fujio, K., Shibuya, M., Sumitomo, S., Shoda, H., Sakaguchi, S., et al. CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc Natl Acad Sci U S A 106 (2009), 13974–13979.
30. Kamanaka, M., Kim, S.T., Wan, Y.Y., Sutterwala, F.S., Lara-Tejero, M., Galan, J.E., et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25 (2006), 941–952.
31. Acosta-Rodriguez, E.V., Rivino, L., Geginat, J., Jarrossay, D., Gattorno, M., Lanzavecchia, A., et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8 (2007), 639–646.
32. Annunziato, F., Cosmi, L., Santarlasci, V., Maggi, L., Liotta, F., Mazzinghi, B., et al. Phenotypic and functional features of human Th17 cells. J Exp Med 204 (2007), 1849–1861.
33. Izcue, A., Hue, S., Buonocore, S., Arancibia-Carcamo, C.V., Ahern, P.P., Iwakura, Y., et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28 (2008), 559–570.
34. Yen, D., Cheung, J., Scheerens, H., Poulet, F., McClanahan, T., McKenzie, B., et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116 (2006), 1310–1316.
35. Kullberg, M.C., Jankovic, D., Feng, C.G., Hue, S., Gorelick, P.L., McKenzie, B.S., et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 203 (2006), 2485–2494.
36. Duerr, R.H., Taylor, K.D., Brant, S.R., Rioux, J.D., Silverberg, M.S., Daly, M.J., et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314 (2006), 1461–1463.
37. Uhlig, H.H., McKenzie, B.S., Hue, S., Thompson, C., Joyce-Shaikh, B., Stepankova, R., et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25 (2006), 309–318.
38. Ahern, P.P., Schiering, C., Buonocore, S., McGeachy, M.J., Cua, D.J., Maloy, K.J., et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33 (2010), 279–288.
39. Coccia, M., Harrison, O.J., Schiering, C., Asquith, M.J., Becher, B., Powrie, F., et al. IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells. J Exp Med 209 (2012), 1595–1609.
40. Caprioli, F., Bose, F., Rossi, R.L., Petti, L., Vigano, C., Ciafardini, C., et al. Reduction of CD68+ macrophages and decreased IL-17 expression in intestinal mucosa of patients with inflammatory bowel disease strongly correlate with endoscopic response and mucosal healing following infliximab therapy. Inflamm Bowel Dis 19 (2013), 729–739.
41. Rivino, L., Gruarin, P., Haringer, B., Steinfelder, S., Lozza, L., Steckel, B., et al. CCR6 is expressed on an IL-10-producing, autoreactive memory T cell population with context-dependent regulatory function. J Exp Med 207 (2010), 565–577.
42. Korn, T., Oukka, M., Kuchroo, V., Bettelli, E., Th17 cells: effector T cells with inflammatory properties. Semin Immunol 19 (2007), 362–371.
43. Awasthi, A., Riol-Blanco, L., Jager, A., Korn, T., Pot, C., Galileos, G., et al. Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 182 (2009), 5904–5908.
44. Banham, A.H., Cell-surface IL-7 receptor expression facilitates the purification of FOXP3(+) regulatory T cells. Trends Immunol 27 (2006), 541–544.
45. Dong, H., Strome, S.E., Matteson, E.L., Moder, K.G., Flies, D.B., Zhu, G., et al. Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest 111 (2003), 363–370.
46. Kuipers, H., Muskens, F., Willart, M., Hijdra, D., van Assema, F.B., Coyle, A.J., et al. Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Immunol 36 (2006), 2472–2482.
47. Day, C.L., Kaufmann, D.E., Kiepiela, P., Brown, J.A., Moodley, E.S., Reddy, S., et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443 (2006), 350–354.
48. Turner, J.E., Steinmetz, O.M., Stahl, R.A., Panzer, U., Targeting of Th1-associated chemokine receptors CXCR3 and CCR5 as therapeutic strategy for inflammatory diseases. Mini Rev Med Chem 7 (2007), 1089–1096.
49. Geginat, J., Larghi, P., Paroni, M., Nizzoli, G., Penatti, A., Pagani, M., et al. The light and the dark sides of Interleukin-10 in immune-mediated diseases and cancer. Cytokine Growth Factor Rev 30 (2016), 87–93.
50. Paroni, M., Magarotto, A., Tartari, S., Nizzoli, G., Larghi, P., Ercoli, G., et al. Uncontrolled IL-17 production by intraepithelial lymphocytes in a case of non-IPEX autoimmune enteropathy. Clin Transl Gastroenterol, 7, 2016, e182.
51. Zielinski, C.E., Mele, F., Aschenbrenner, D., Jarrossay, D., Ronchi, F., Gattorno, M., et al. Pathogen-induced human TH17 cells produce IFN-gamma or IL-10 and are regulated by IL-1beta. Nature 484 (2012), 514–518.
52. Abraham, C., Cho, J.H., IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease. Annu Rev Med 60 (2009), 97–110.
53. Ramesh, R., Kozhaya, L., McKevitt, K., Djuretic, I.M., Carlson, T.J., Quintero, M.A., et al. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J Exp Med 211 (2014), 89–104.
54. Heinemann, C., Heink, S., Petermann, F., Vasanthakumar, A., Rothhammer, V., Doorduijn, E., et al. IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1. Nat Commun, 5, 2014, 3770.
55. Gocke, A.R., Cravens, P.D., Ben, L.H., Hussain, R.Z., Northrop, S.C., Racke, M.K., et al. T-bet regulates the fate of Th1 and Th17 lymphocytes in autoimmunity. J Immunol 178 (2007), 1341–1348.