Digestive Diseases and Sciences

, Volume 58, Issue 6, pp 1497–1506 | Cite as

T Cell Co-Stimulatory Molecules: A Co-conspirator in the Pathogenesis of Eosinophilic Esophagitis?



Eosinophilic esophagitis (EoE) has become a common gastrointestinal disease. It is characterized by severe eosinophil infiltration in the esophagus. EoE is strongly associated with food allergy, asthma, atopic dermatitis, and other allergic diseases. T lymphocytes, especially Th2 cells, play an instrumental role in the development of allergic inflammation. Recent studies have shown that the ligation of co-stimulatory molecules contributes to the activation, differentiation, and proliferation of T cells. In this review, we will discuss the growing evidence of co-stimulatory molecules including OX40, Light, and HVEM in the pathogenesis of Th2-driven EoE. Our goal is to provide the rationale for the development of novel therapy therapies that target co-stimulatory molecules.


Co-stimulatory molecules Eosinophilic esophagitis HVEM Light OX40 Th2 cells 


  1. 1.
    Noel RJ, Putnam PE, Rothenberg ME. Eosinophilic esophagitis. N Engl J Med. 2004;351:940–941.PubMedCrossRefGoogle Scholar
  2. 2.
    Nielsen RG, Husby S. Eosinophilic oesophagitis: epidemiology, clinical aspects, and association to allergy. J Pediatr Gastroenterol Nutr. 2007;45:281–289.PubMedCrossRefGoogle Scholar
  3. 3.
    Hurrell JM, Genta RM, Dellon ES. Prevalence of esophageal eosinophilia varies by climate zone in the United States. Am J Gastroenterol. 2012;107:698–706.PubMedCrossRefGoogle Scholar
  4. 4.
    Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology. 1995;109:1503–1512.PubMedCrossRefGoogle Scholar
  5. 5.
    Eroglu Y, Lu H, Terry A, et al. Pediatric eosinophilic esophagitis: single-center experience in northwestern USA. Pediatr Int. 2009;51:612–616.PubMedCrossRefGoogle Scholar
  6. 6.
    DeBrosse CW, Rothenberg ME. Allergy and eosinophil-associated gastrointestinal disorders (EGID). Curr Opin Immunol. 2008;20:703–708.PubMedCrossRefGoogle Scholar
  7. 7.
    Kapel RC, Miller JK, Torres C, Aksoy S, Lash R, Katzka DA. Eosinophilic esophagitis: a prevalent disease in the United States that affects all age groups. Gastroenterology. 2008;134:1316–1321.PubMedCrossRefGoogle Scholar
  8. 8.
    Fryer AD, Stein LH, Nie Z, et al. Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction. J Clin Invest. 2006;116:228–236.PubMedCrossRefGoogle Scholar
  9. 9.
    Aceves SS, Newbury RO, Dohil R, Bastian JF, Broide DH. Esophageal remodeling in pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2007;119:206–212.PubMedCrossRefGoogle Scholar
  10. 10.
    Chehade M, Sampson HA, Morotti RA, Magid MS. Esophageal subepithelial fibrosis in children with eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2007;45:319–328.PubMedCrossRefGoogle Scholar
  11. 11.
    Li-Kim-Moy JP, Tobias V, Day AS, Leach S, Lemberg DA. Esophageal subepithelial fibrosis and hyalinization are features of eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2011;52:147–153.PubMedCrossRefGoogle Scholar
  12. 12.
    Dellon ES. Eosinophilic esophagitis: diagnostic tests and criteria. Curr Opin Gastroenterol. 2012;28:382–388.PubMedCrossRefGoogle Scholar
  13. 13.
    Druilhe A, Létuvé S, Pretolani M. Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis. 2003;8:481–495.PubMedCrossRefGoogle Scholar
  14. 14.
    Dohil R, Newbury R, Fox L, Bastian J, Aceves S. Oral viscous budesonide is effective in children with eosinophilic esophagitis in a randomized, placebo-controlled trial. Gastroenterology. 2010;139:418–429.PubMedCrossRefGoogle Scholar
  15. 15.
    Konikoff MR, Noel RJ, Blanchard C, et al. A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology. 2006;131:1381–1391.PubMedCrossRefGoogle Scholar
  16. 16.
    Blanchard C, Wang N, Rothenberg ME. Eosinophilic esophagitis: pathogenesis, genetics, and therapy. J Allergy Clin Immunol. 2006;118:1054–1059.PubMedCrossRefGoogle Scholar
  17. 17.
    Blanchard C, Stucke EM, Burwinkel K, et al. Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. J Immunol. 2010;184:4033–4041.PubMedCrossRefGoogle Scholar
  18. 18.
    Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441–446.PubMedCrossRefGoogle Scholar
  19. 19.
    Rothenberg ME. Biology and treatment of eosinophilic esophagitis. Gastroenterology. 2009;137:1238–1249.PubMedCrossRefGoogle Scholar
  20. 20.
    Blanchard C, Wang N, Stringer KF, et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J Clin Invest. 2006;116:536–547.PubMedCrossRefGoogle Scholar
  21. 21.
    Ziegler SF. The role of thymic stromal lymphopoietin (TSLP) in allergic disorders. Curr Opin Immunol. 2010;22:795–799.PubMedCrossRefGoogle Scholar
  22. 22.
    Rothenberg ME, Spergel JM, Sherrill JD, et al. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet. 2010;42:289–291.PubMedCrossRefGoogle Scholar
  23. 23.
    Chetty R, Gatter K. CD3: structure, function and role of immunostaining in clinical practice. J Pathol. 1994;173:303–307.PubMedCrossRefGoogle Scholar
  24. 24.
    Grunow R, Volk HD, Schwaab J, Barthelmes H, Lande L, von Baehr R. Masking of pan T cell markers in patients with autoimmune diseases. Dermatol Monatsschr. 1987;173:390–399.PubMedGoogle Scholar
  25. 25.
    Neurath MF, Finotto S, Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nat Med. 2002;8:567–573.PubMedCrossRefGoogle Scholar
  26. 26.
    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138–146.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010;28:445–489.PubMedCrossRefGoogle Scholar
  28. 28.
    Omori M, Ziegler S. Induction of IL-4 expression in CD4(+) T cells by thymic stromal lymphopoietin. J Immunol.. 2007;178:1396–1404.PubMedGoogle Scholar
  29. 29.
    Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485–517.PubMedCrossRefGoogle Scholar
  30. 30.
    Paul WE. What determines Th2 differentiation, in vitro and in vivo? Immunol Cell Biol. 2010;88(3):236–239.PubMedCrossRefGoogle Scholar
  31. 31.
    Straumann A, Bauer M, Fischer B, Blaser K, Simon HU. Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response. J Allergy Clin Immunol. 2001;108:954–961.PubMedCrossRefGoogle Scholar
  32. 32.
    Bullock JZ, Villanueva JM, Blanchard C, et al. Interplay of adaptive Th2 immunity with eotaxin-3/c-C chemokine receptor 3 in eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2007;45:22–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Stein ML, Collins MH, Villanueva JM, et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol. 2006;118:1312–1319.PubMedCrossRefGoogle Scholar
  34. 34.
    Syrbe U, Siveke J, Hamann A. Th1/Th2 subsets: distinct differences in homing and chemokine receptor expression? Springer Semin Immunopathol. 1999;21:263–285.PubMedCrossRefGoogle Scholar
  35. 35.
    Amerio P, Frezzolini A, Feliciani C, et al. Eotaxins and CCR3 receptor in inflammatory and allergic skin diseases: therapeutical implications. Curr Drug Targets Inflamm Allergy. 2003;2:81–94.PubMedCrossRefGoogle Scholar
  36. 36.
    Ponath PD, Qin S, Ringler DJ, et al. Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest. 1996;97:604–612.PubMedCrossRefGoogle Scholar
  37. 37.
    Kitaura M, Nakajima T, Imai T, et al. Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3. J Biol Chem. 1996;271:7725–7730.PubMedCrossRefGoogle Scholar
  38. 38.
    Moqbel R, Ying S, Barkans J, et al. Identification of messenger RNA for IL-4 in human eosinophils with granule localization and release of the translated product. J Immunol. 1995;155:4939–4947.PubMedGoogle Scholar
  39. 39.
    Möller GM, de Jong TA, van der Kwast TH, et al. Immunolocalization of interleukin-4 in eosinophils in the bronchial mucosa of atopic asthmatics. Am J Respir Cell Mol Biol. 1996;14:439–443.PubMedCrossRefGoogle Scholar
  40. 40.
    Bandeira-Melo C, Sugiyama K, Woods LJ, Weller PF. Cutting edge: eotaxin elicits rapid vesicular transport-mediated release of preformed IL-4 from human eosinophils. J Immunol. 2001;166:4813–4817.PubMedGoogle Scholar
  41. 41.
    Dubois GR, Bruijnzeel-Koomen CA, Bruijnzeel PL. IL-4 induces chemotaxis of blood eosinophils from atopic dermatitis patients, but not from normal individuals. J Invest Dermatol. 1994;102:843–846.PubMedCrossRefGoogle Scholar
  42. 42.
    Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147–174.PubMedCrossRefGoogle Scholar
  43. 43.
    Blanchard C, Stucke EM, Rodriguez-Jimenez B, et al. A striking local esophageal cytokine expression profile in eosinophilic esophagitis. J Allergy Clin Immunol. 2011;127:208–217.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhu X, Wang M, Mavi P, et al. Interleukin-15 expression is increased in human eosinophilic esophagitis and mediates pathogenesis in mice. Gastroenterology. 2010;139:182–193.PubMedCrossRefGoogle Scholar
  45. 45.
    Spergel JM, Rothenberg ME, Collins MH, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2012;129:456–463.PubMedCrossRefGoogle Scholar
  46. 46.
    Felix NJ, Suri A, Salter-Cid L, et al. Targeting lymphocyte co-stimulation: from bench to bedside. Autoimmunity. 2010;43:514–525.PubMedCrossRefGoogle Scholar
  47. 47.
    Chambers CA, Allison JP. Co-stimulation in T cell responses. Curr Opin Immunol. 1997;9:396–404.PubMedCrossRefGoogle Scholar
  48. 48.
    Green JM, Noel PJ, Sperling AI, et al. Absence of B7-dependent responses in CD28-deficient mice. Immunity. 1994;1:501–508.PubMedCrossRefGoogle Scholar
  49. 49.
    Botturi K, Lacoeuille Y, Cavaillès A, Vervloet D, Magnan A. Differences in allergen-induced T cell activation between allergic asthma and rhinitis: role of CD28, ICOS and CTLA-4. Respir Res. 2011;12:25.PubMedCrossRefGoogle Scholar
  50. 50.
    Shilling RA, Clay BS, Tesciuba AG, et al. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo. Cell Immunol. 2009;259:177–184.PubMedCrossRefGoogle Scholar
  51. 51.
    Simpson TR, Quezada SA, Allison JP. Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS). Curr Opin Immunol. 2010;22:326–332.PubMedCrossRefGoogle Scholar
  52. 52.
    MacDonald AS, Straw AD, Dalton NM, Pearce EJ. Cutting edge: Th2 response induction by dendritic cells: a role for CD40. J Immunol. 2002;168:537–540.PubMedGoogle Scholar
  53. 53.
    Poudrier J, van Essen D, Morales-Alcelay S, Leanderson T, Bergthorsdottir S, Gray D. CD40 ligand signals optimize T helper cell cytokine production: role in Th2 development and induction of germinal centers. Eur J Immunol. 1998;28:3371–3383.PubMedCrossRefGoogle Scholar
  54. 54.
    Le-Carlson M, Seki S, Abarbanel D, Quiros A, Cox K, Nadeau KC. Markers of Antigen Presentation and Activation on Eosinophils and T-Cells in the Esophageal Tissue of Patients with Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr. Epub. 10 Oct 2012.Google Scholar
  55. 55.
    Croft M. The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol. 2009;9:271–285.PubMedCrossRefGoogle Scholar
  56. 56.
    Croft M, So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev. 2009;229:173–191.PubMedCrossRefGoogle Scholar
  57. 57.
    Weinberg AD, Wegmann KW, Funatake C, Whitham RH. Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis. J Immunol. 1999;162:1818–1826.PubMedGoogle Scholar
  58. 58.
    Murata K, Ishii N, Takano H, et al. Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand. J Exp Med. 2000;191:365–374.PubMedCrossRefGoogle Scholar
  59. 59.
    Arch RH, Thompson CB. 4–1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB. Mol Cell Biol. 1998;18:558–565.PubMedGoogle Scholar
  60. 60.
    Kawamata S, Hori T, Imura A, Takaori-Kondo A, Uchiyama T. Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation. J Biol Chem. 1998;273:5808–5814.PubMedCrossRefGoogle Scholar
  61. 61.
    Lane P. Role of OX40 signals in coordinating CD4 T cell selection, migration, and cytokine differentiation in T helper (Th)1 and Th2 cells. J Exp Med. 2000;191:201–206.PubMedCrossRefGoogle Scholar
  62. 62.
    Kim MY, Bekiaris V, McConnell FM, Gaspal FM, Raykundalia C, Lane PJ. OX40 signals during priming on dendritic cells inhibit CD4 T cell proliferation: IL-4 switches off OX40 signals enabling rapid proliferation of Th2 effectors. J Immunol. 2005;174:1433–1437.PubMedGoogle Scholar
  63. 63.
    Salek-Ardakani S, Song J, Halteman BS, et al. OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. J Exp Med. 2003;198(2):315–324.PubMedCrossRefGoogle Scholar
  64. 64.
    Ishii N, Ndhlovu LC, Murata K, Sato T, Kamanaka M, Sugamura K. OX40 (CD134) and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses. Eur J Immunol. 2003;33:2372–2381.PubMedCrossRefGoogle Scholar
  65. 65.
    MacPhee IA, Yagita H, Oliveira DB. Blockade of OX40-ligand after initial triggering of the T helper 2 response inhibits mercuric chloride-induced autoimmunity. Immunology. 2006;117:402–408.PubMedCrossRefGoogle Scholar
  66. 66.
    Fukushima A, Yamaguchi T, Ishida W, Fukata K, Yagita H, Ueno H. Roles of OX40 in the development of murine experimental allergic conjunctivitis: exacerbation and attenuation by stimulation and blocking of OX40. Invest Ophthalmol Vis Sci. 2006;47:657–663.PubMedCrossRefGoogle Scholar
  67. 67.
    Rogers PR, Song J, Gramaglia I, Killeen N, Croft M. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity. 2001;15:445–455.PubMedCrossRefGoogle Scholar
  68. 68.
    Gaspal F, Withers D, Saini M, et al. Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-deficient mice. J Exp Med. 2011;208:1579–1584.PubMedCrossRefGoogle Scholar
  69. 69.
    Sugamura K, Ishii N, Weinberg AD. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat Rev Immunol. 2004;4:420–431.PubMedCrossRefGoogle Scholar
  70. 70.
    Morris NP, Peters C, Montler R, et al. Development and characterization of recombinant human Fc:OX40L fusion protein linked via a coiled-coil trimerization domain. Mol Immunol. 2007;44:3112–3121.PubMedCrossRefGoogle Scholar
  71. 71.
    Wang J, Fu YX. The role of LIGHT in T cell-mediated immunity. Immunol Res. 2004;30:201–214.PubMedCrossRefGoogle Scholar
  72. 72.
    Murphy KM, Nelson CA, Sedý JR. Balancing co-stimulation and inhibition with BTLA and HVEM. Nat Rev Immunol. 2006;6:671–681.PubMedCrossRefGoogle Scholar
  73. 73.
    Steinberg MW, Cheung TC, Ware CF. The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol Rev. 2011;244:169–187.PubMedCrossRefGoogle Scholar
  74. 74.
    Shui JW, Steinberg MW, Kronenberg M. Regulation of inflammation, autoimmunity, and infection immunity by HVEM-BTLA signaling. J Leukoc Biol. 2011;89:517–523.PubMedCrossRefGoogle Scholar
  75. 75.
    Wang J, Lo JC, Foster A, et al. The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT. J Clin Invest. 2001;108:1771–1780.PubMedGoogle Scholar
  76. 76.
    Soroosh P, Doherty TA, So T, et al. Herpesvirus entry mediator (TNFRSF14) regulates the persistence of T helper memory cell populations. J Exp Med. 2011;208:797–809.PubMedCrossRefGoogle Scholar
  77. 77.
    Doherty TA, Soroosh P, Khorram N, et al. The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat Med. 2011;17:596–603.PubMedCrossRefGoogle Scholar
  78. 78.
    Aceves SS, Newbury RO, Chen D, et al. Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids. Allergy. 2010;65:109–116.PubMedCrossRefGoogle Scholar
  79. 79.
    Abonia JP, Franciosi JP, Rothenberg ME. TGF-β1: mediator of a feedback loop in eosinophilic esophagitis—or should we really say mastocytic esophagitis? J Allergy Clin Immunol. 2010;126:1205–1207.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of PediatricsCase Western Reserve University School of MedicineClevelandUSA
  2. 2.Department of PediatricsOregon Health and Science UniversityPortlandUSA

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