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Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite 4065, Los Angeles, CA, 90048, USA
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Abstract
Expression of NK cell markers identifies pro-inflammatory T cell subsets in the liver and intestinal immune compartments. Specifically, CD161 is expressed on Th17 cells which play an important role in the regulation of mucosal inflammation. In this study, we characterized human peripheral blood CD161+ T cells as an effector population partially resembling a gut T cell phenotype. CD161+ CD4+ T cells express the gut-associated TNF family member, LIGHT, and respond to crosslinking of DR3, a receptor to another gut-associated cytokine, TL1A. Robust IFN-γ production in response to DR3 signaling correlated with enhanced expression of surface DR3 on CD161+ T cells and co-stimulation with IL12 and IL18. CD161+ T cell effector function was directly demonstrated by activation of responder monocytes in co-culture leading to CD40 upregulation and CD14 downregulation. CD161+ T cells reciprocally responded to activated monocytes, inducing expression of activation marker, CD69, and production of IL2 and IFN-γ, further demonstrating effective CD161+ T cell cross-talk with monocytes. Finally, CD161 defined a subset of T cells that co-express CD56, a second NK marker. Our findings implicate human CD161+ T cells in gut-associated signaling mechanisms, and suggest a monocyte mediated effector function in mucosal inflammation.
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1. D.Q. Shih S.R. Targan 2008 Immunopathogenesis of inflammatory bowel disease World J Gastroenterol 14 390–400.
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2. D.Q. Shih S.R. Targan D. McGovern 2008 Recent advances in IBD pathogenesis: genetics and immunobiology Curr Gastroenterol Rep 10 568–575.
-
3. S.R. Targan R.L. Deem M. Liu S. Wang A. Nel 1995 Definition of a lamina propria T cell responsive state. Enhanced cytokine responsiveness of T cells stimulated through the CD2 pathway J Immunol 154 664–675.
-
4. D.Q. Shih K.S. Michelsen R.J. Barrett E. Biener-Ramanujan R. Gonsky X. Zhang S.R. Targan 2010 Insights into TL1A and IBD pathogenesis Adv Exp Med Biol 691 279–288.
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5. S.R. Targan S.B. Hanauer S.J. van Deventer L. Mayer D.H. Present T. Braakman K.L. DeWoody T.F. Schaible P.J. Rutgeerts 1997 A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group N Engl J Med 337 1029–1035.
-
6. P. Rutgeerts W.J. Sandborn B.G. Feagan W. Reinisch A. Olson J. Johanns S. Travers D. Rachmilewitz S.B. Hanauer G.R. Lichtenstein W.J. de Villiers D. Present B.E. Sands J.F. Colombel 2005 Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 353 2462–2476.
-
7. O. Cohavy J. Zhou S.W. Granger C.F. Ware S.R. Targan 2004 LIGHT expression by mucosal T cells may regulate IFN-gamma expression in the intestine J Immunol 173 251–258.
-
8. R.M. Locksley N. Killeen M.J. Lenardo 2001 The TNF and TNF receptor superfamilies: integrating mammalian biology Cell 104 487–501.
-
9. D.N. Mauri R. Ebner R.I. Montgomery K.D. Kochel T.C. Cheung G.L. Yu S. Ruben M. Murphy R.J. Eisenberg G.H. Cohen P.G. Spear C.F. Ware 1998 LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator Immunity 8 21–30.
-
10. B.S. Kwon K.B. Tan J. Ni K.O. Oh Z.H. Lee K.K. Kim Y.J. Kim S. Wang R. Gentz G.L. Yu J. Harrop S.D. Lyn C. Silverman T.G. Porter A. Truneh P.R. Young 1997 A newly identified member of the tumor necrosis factor receptor superfamily with a wide tissue distribution and involvement in lymphocyte activation J Biol Chem 272 14272–14276.
-
11. A. Futterer K. Mink A. Luz M.H. Kosco-Vilbois K. Pfeffer 1998 The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues Immunity 9 59–70.
-
12. I.A. Rooney K.D. Butrovich A.A. Glass S. Borboroglu C.A. Benedict J.C. Whitbeck G.H. Cohen R.J. Eisenberg C.F. Ware 2000 The lymphotoxin-beta receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells J Biol Chem 275 14307–14315.
-
13. K.M. Murphy C.A. Nelson J.R. Sedy 2006 Balancing co-stimulation and inhibition with BTLA and HVEM Nat Rev Immunol 6 671–681.
-
14. T.S. Migone J. Zhang X. Luo L. Zhuang C. Chen B. Hu J.S. Hong J.W. Perry S.F. Chen J.X. Zhou Y.H. Cho S. Ullrich P. Kanakaraj J. Carrell E. Boyd H.S. Olsen G. Hu L. Pukac D. Liu J. Ni S. Kim R. Gentz P. Feng P.A. Moore S.M. Ruben P. Wei 2002 TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator Immunity 16 479–492.
-
15. L. Wen L. Zhuang X. Luo P. Wei 2003 TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells J Biol Chem 278 39251–39258.
-
16. R. Fayad M.I. Brand D. Stone A. Keshavarzian L. Qiao 2006 Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells Eur J Immunol 36 2215–2222.
-
17. R.B. Shaikh S. Santee S.W. Granger K. Butrovich T. Cheung M. Kronenberg H. Cheroutre C.F. Ware 2001 Constitutive expression of LIGHT on T cells leads to lymphocyte activation, inflammation, and tissue destruction J Immunol 167 6330–6337.
-
18. J. Wang J.C. Lo A. Foster P. Yu H.M. Chen Y. Wang K. Tamada L. Chen Y.X. Fu 2001 The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT J Clin Invest 108 1771–1780.
-
19. F. Mackay J.L. Browning P. Lawton S.A. Shah M. Comiskey A.K. Bhan E. Mizoguchi C. Terhorst S.J. Simpson 1998 Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis Gastroenterology 115 1464–1475.
-
20. O. Cohavy J. Zhou C.F. Ware S.R. Targan 2005 LIGHT is constitutively expressed on T and NK cells in the human gut and can be induced by CD2-mediated signaling J Immunol 174 646–653.
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21. G. Bamias C. Martin 3rd M. Marini S. Hoang M. Mishina W.G. Ross M.A. Sachedina C.M. Friel J. Mize S.J. Bickston T.T. Pizarro P. Wei F. Cominelli 2003 Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease J Immunol 171 4868–4874.
-
22. J.L. Prehn S. Mehdizadeh C.J. Landers X. Luo S.C. Cha P. Wei S.R. Targan 2004 Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation Clin Immunol 112 66–77.
-
23. G. Bamias M. Mishina M. Nyce W.G. Ross G. Kollias J. Rivera-Nieves T.T. Pizarro F. Cominelli 2006 Role of TL1A and its receptor DR3 in two models of chronic murine ileitis Proc Natl Acad Sci U S A 103 8441–8446.
-
24. H. Takedatsu K.S. Michelsen B. Wei C.J. Landers L.S. Thomas D. Dhall J. Braun S.R. Targan 2008 TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation Gastroenterology 135 552–567.
-
25. F. Meylan Y.J. Song I. Fuss S. Villarreal E. Kahle I.J. Malm K. Acharya H.L. Ramos L. Lo M.M. Mentink-Kane T.A. Wynn T.S. Migone W. Strober R.M. Siegel 2011 The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation Mucosal Immunol 4 172–185.
-
26. D.Q. Shih R. Barrett X. Zhang N. Yeager H.W. Koon P. Phaosawasdi Y. Song B. Ko M.H. Wong K.S. Michelsen G. Martins C. Pothoulakis S.R. Targan 2011 Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis PLoS One 6 e16090.
-
27. S.W. Granger K.D. Butrovich P. Houshmand W.R. Edwards C.F. Ware 2001 Genomic characterization of LIGHT reveals linkage to an immune response locus on chromosome 19p13.3 and distinct isoforms generated by alternate splicing or proteolysis J Immunol 167 5122–5128.
-
28. J.D. Rioux M.S. Silverberg M.J. Daly A.H. Steinhart R.S. McLeod A.M. Griffiths T. Green T.S. Brettin V. Stone S.B. Bull A. Bitton C.N. Williams G.R. Greenberg Z. Cohen E.S. Lander T.J. Hudson K.A. Siminovitch 2000 Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci Am J Hum Genet 66 1863–1870.
-
29. J. O'Keeffe D.G. Doherty T. Kenna K. Sheahan D.P. O'Donoghue J.M. Hyland C. O'Farrelly 2004 Diverse populations of T cells with NK cell receptors accumulate in the human intestine in health and in colorectal cancer Eur J Immunol 34 2110–2119.
-
30. T. Kenna L. Golden-Mason S.A. Porcelli Y. Koezuka J.E. Hegarty C. O'Farrelly D.G. Doherty 2003 NKT cells from normal and tumor-bearing human livers are phenotypically and functionally distinct from murine NKT cells J Immunol 171 1775–1779.
-
31. O. Cohavy S.R. Targan 2007 CD56 marks an effector T cell subset in the human intestine J Immunol 178 5524–5532.
-
32. J.R. Ortaldo R.T. Winkler-Pickett H. Yagita H.A. Young 1991 Comparative studies of CD3- and CD3+ CD56+ cells: examination of morphology, functions, T cell receptor rearrangement, and pore-forming protein expression Cell Immunol 136 486–495.
-
33. T. Iiai H. Watanabe T. Suda H. Okamoto T. Abo K. Hatakeyama 2002 CD161+ T (NT) cells exist predominantly in human intestinal epithelium as well as in liver Clin Exp Immunol 129 92–98.
-
34. D.G. Doherty S. Norris L. Madrigal-Estebas G. McEntee O. Traynor J.E. Hegarty C. O'Farrelly 1999 The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns J Immunol 163 2314–2321.
-
35. M.A. Kleinschek K. Boniface S. Sadekova J. Grein E.E. Murphy S.P. Turner L. Raskin B. Desai W.A. Faubion R. de Waal Malefyt R.H. Pierce T. McClanahan R.A. Kastelein 2009 Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation J Exp Med 206 525–534.
-
36. S. Norris D.G. Doherty C. Collins G. McEntee O. Traynor J.E. Hegarty C. O'Farrelly 1999 Natural T cells in the human liver: cytotoxic lymphocytes with dual T cell and natural killer cell phenotype and function are phenotypically heterogenous and include Valpha24-JalphaQ and gammadelta T cell receptor bearing cells Hum Immunol 60 20–31.
-
37. U. Gunther J.A. Holloway J.N. Gordon A. Knight V. Chance N.A. Hanley D.I. Wilson R. French J. Spencer H. Steer G. Anderson T.T. MacDonald 2005 Phenotypic characterization of CD3–7+ cells in developing human intestine and an analysis of their ability to differentiate into T cells J Immunol 174 5414–5422.
-
38. N. Musha Y. Yoshida S. Sugahara S. Yamagiwa T. Koya H. Watanabe K. Hatakeyama T. Abo 1998 Expansion of CD56+ NK T and gamma delta T cells from cord blood of human neonates Clin Exp Immunol 113 220–228.
-
39. M.J. Loza P. Luppi K. Kiefer E.S. Martin J.L. Szczytkowski B. Perussia 2005 Human peripheral CD2-/lo T cells: an extrathymic population of early differentiated, developing T cells Int Immunol 17 1213–1225.
-
40. D.Q. Shih L.Y. Kwan V. Chavez O. Cohavy R. Gonsky E.Y. Chang C. Chang C.O. Elson S.R. Targan 2009 Microbial induction of inflammatory bowel disease associated gene TL1A (TNFSF15) in antigen presenting cells Eur J Immunol 39 3239–3250.
-
41. K.A. Papadakis J.L. Prehn C. Landers Q. Han X. Luo S.C. Cha P. Wei S.R. Targan 2004 TL1A synergizes with IL-12 and IL-18 to enhance IFN-gamma production in human T cells and NK cells J Immunol 172 7002–7007.
-
42. S. Heidenreich M. Schmidt C. August P. Cullen A. Rademaekers H.G. Pauels 1997 Regulation of human monocyte apoptosis by the CD14 molecule J Immunol 159 3178–3188.
-
43. R. Mahanonda N. Sa-Ard-Iam O. Charatkulangkun A. Promsudthi R.E. Schifferle K. Yongvanichit S. Pichyangkul 2004 Monocyte activation by Porphyromonas gingivalis LPS in aggressive periodontitis with the use of whole-blood cultures J Dent Res 83 540–545.
-
44. R. Landmann H.P. Knopf S. Link S. Sansano R. Schumann W. Zimmerli 1996 Human monocyte CD14 is upregulated by lipopolysaccharide Infect Immun 64 1762–1769.
-
45. L. Cosmi R. De Palma V. Santarlasci L. Maggi M. Capone F. Frosali G. Rodolico V. Querci G. Abbate R. Angeli L. Berrino M. Fambrini M. Caproni F. Tonelli E. Lazzeri P. Parronchi F. Liotta E. Maggi S. Romagnani F. Annunziato 2008 Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor J Exp Med 205 1903–1916.
-
46. J.A. Harrop M. Reddy K. Dede M. Brigham-Burke S. Lyn K.B. Tan C. Silverman C. Eichman R. DiPrinzio J. Spampanato T. Porter S. Holmes P.R. Young A. Truneh 1998 Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines J Immunol 161 1786–1794.
-
47. J.L. Prehn L.S. Thomas C.J. Landers Q.T. Yu K.S. Michelsen S.R. Targan 2007 The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells J Immunol 178 4033–4038.
-
48. N. Kamada T. Hisamatsu H. Honda T. Kobayashi H. Chinen T. Takayama M.T. Kitazume S. Okamoto K. Koganei A. Sugita T. Kanai T. Hibi 2010 TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn's disease Inflamm Bowel Dis 16 568–575.
-
49. K.A. Papadakis C. Landers J. Prehn E.A. Kouroumalis S.T. Moreno J.C. Gutierrez-Ramos M.R. Hodge S.R. Targan 2003 CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or T-regulatory 1 cytokine profile J Immunol 171 159–165.
-
50. K.A. Papadakis D. Zhu J.L. Prehn C. Landers A. Avanesyan G. Lafkas S.R. Targan 2005 Dominant role for TL1A/DR3 pathway in IL-12 plus IL-18-induced IFN-gamma production by peripheral blood and mucosal CCR9+ T lymphocytes J Immunol 174 4985–4990.
-
51. E. Huarte J.R. Cubillos-Ruiz Y.C. Nesbeth U.K. Scarlett D.G. Martinez X.A. Engle W.F. Rigby P.A. Pioli P.M. Guyre J.R. Conejo-Garcia 2008 PILAR is a novel modulator of human T-cell expansion Blood 112 1259–1268.
-
52. M.T. Abreu-Martin S.R. Targan 1996 Regulation of immune responses of the intestinal mucosa Crit Rev Immunol 16 277–309.
-
53. R. Duchmann I. Kaiser E. Hermann W. Mayet K. Ewe K.H. Meyer zum Buschenfelde 1995 Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD) Clin Exp Immunol 102 448–455.
-
54. F. Lambolez M.L. Arcangeli A.M. Joret V. Pasqualetto C. Cordier J.P. Di Santo B. Rocha S. Ezine 2006 The thymus exports longlived fully committed T cell precursors that can colonize primary lymphoid organs Nat Immunol 7 76–82.
Dr. Dunay, Ildiko Rita
Magdeburg, Germany
E-mail: ildiko.dunay@med.ovgu.de
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