CD8+ T Cells Play a Key Role in the Development of Allergic Lung Inflammation

  • Nobuaki Miyahara
  • Erwin W. Gelfand
Part of the Allergy Frontiers book series (ALLERGY, volume 2)


Asthma is a complex syndrome involving many cell types, effector molecules, and mediators. CD4+ T cells are known to play a pivotal role in the initiation of the disease. Here, the role of the CD8+ T cells is highlighted, both in the triggering of lung allergic responses and in the negative regulation of these responses.


Major Histocompatibility Complex Class Airway Inflammation Allergy Clin Immunol Airway Hyperresponsiveness Allergic Airway Inflammation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Busse WW, Coffman RL, Gelfand EW, Kay AB, Rosenwasser LJ (1995) Mechanisms of persistent airway inflammation in asthma: a role for T cells and T-cell products. Am J Resp Crit Care Med 152:388–393PubMedGoogle Scholar
  2. 2.
    Cohn L, Tepper JS, Bottomly K (1998) IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells. J Immunol 161:3813–3816PubMedGoogle Scholar
  3. 3.
    Gavett SH, Chen X, Finkelman F, Wills-Karp M (1994) Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia. Am J Resp Cell Mol Biol 10:587–593Google Scholar
  4. 4.
    Grunig G, Wamock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB (1998) Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282:2261–2263PubMedCrossRefGoogle Scholar
  5. 5.
    McKenzie GJ, Emson CL, Bell SE, Anderson S, Fallon P, Zurawski G, Murray R, Grencis R, McKenzie AN (1998) Impaired development of Th2 cells in IL-13-deficient mice. Immunity 9:423–432PubMedCrossRefGoogle Scholar
  6. 6.
    Swain SL, Croft M, Dubey C, Haynes L, Rogers P, Zhang X, Bradley LM (1996) From naive to memory T cells. Immunol Rev 150:143–167PubMedCrossRefGoogle Scholar
  7. 7.
    Zinkernagel RM, Bachmann MF, Kuendig TE, Oehen S, Pircher H, Hengartner H (1996) On immunological memory. Annu Rev Immunol 14:333–367PubMedCrossRefGoogle Scholar
  8. 8.
    Sad S, Krishnan L (2003) Maintenance and attrition of T-cell memory. Crit Rev Immunol 23:129–147PubMedCrossRefGoogle Scholar
  9. 9.
    Croft M, Carter L, Swain SL, Dutton RW (1994) Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J Exp Med 180:1715–1728PubMedCrossRefGoogle Scholar
  10. 10.
    Gonzalez MC, Diaz P, Galleguillos FR, Ancic P, Cromwell O, Kay AB (1987) Allergeninduced recruitment of bronchoalveolar helper (OKT4) and suppressor (OKT8) T-cells in asthma. Relative increases in OKT8 cells in single early responders compared with those in late-phase responders. Am Rev Resp Dis 136:600–604PubMedGoogle Scholar
  11. 11.
    Miyata S, Matsuyama T, Kodama T, Nishioka Y, Kuribayashi K, Takeda K, Akira S, Sugita M (1999) STAT6 deficiency in a mouse model of allergen-induced airways inflammation abolishes eosinophilia but induces infiltration of CD8+ T cells. Clin Exp Allergy 29:114–123PubMedCrossRefGoogle Scholar
  12. 12.
    Hamelmann E, Oshiba A, Paluh J, Bradley K, Loader J, Potter TA, Larsen GL, Gelfand EW (1996) Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a murine model of airway sensitization. J Exp Med 183:1719–1729PubMedCrossRefGoogle Scholar
  13. 13.
    Cho SH, Stanciu LA, Begishivili T, Bates PJ, Holgate ST, Johnston SL (2002) Peripheral blood CD4+ and CD8+ T cell type 1 and type 2 cytokine production in atopic and normal subjects. Clin Exp Allergy 32:427–433PubMedCrossRefGoogle Scholar
  14. 14.
    Cho SH, Stanciu LA, Holgate ST, Johnston SL (2005) Increased interleukin-4, 5 and interferon-(gamma) in airway CD4+ and CD8+ T cells in atopic asthma. Am J Resp Crit Care Med 171: 224–230PubMedCrossRefGoogle Scholar
  15. 15.
    Miyahara N, Takeda K, Kodama T, Joetham A, Taube C, Park JW, Miyahara S, Balhorn A, Dakhama A, Gelfand EW (2004) Contribution of antigen-primed CD8+ T cells to the development of airway hyperresponsiveness and inflammation is associated with IL-13. J Immunol 172:2549–2558PubMedGoogle Scholar
  16. 16.
    Miyahara N, Swanson BJ, Takeda K, Taube C, Miyahara S, Kodama T, Dakhama A, Ott VL, Gelfand EW (2004) Effector CD8(+) T cells mediate inflammation and airway hyperrespon-siveness. Nat Med 10:865–869PubMedCrossRefGoogle Scholar
  17. 17.
    Isogai S, Miyata S, Taha R, Yoshizawa Y, Martin JG, Hamid Q (2004) CD8+ alphabeta T cells can mediate late airway responses and airway eosinophilia in rats. J Allergy Clin Immunol 114:1345–1352PubMedCrossRefGoogle Scholar
  18. 18.
    Cerwenka A, Morgan TM, Harmsen AG, Dutton RW (2004) Tc2 cells respond to soluble antigen in the respiratory tract and induce lung eosinophilia and bronchial hyperresponsiveness. Eur J Immunol 34:2599–2608CrossRefGoogle Scholar
  19. 19.
    Erard F, Wild MT, Garcia-Sanz JA, LeGros G (1993) CD8+ lymphocytes can develop into non-cytolytic CD8-CD4-cells which produce IL-4, IL-5, IL-10, and help B cells. Science 260:1802–1805PubMedCrossRefGoogle Scholar
  20. 20.
    Sad S, Marcotte R, Mosmann TR (1995) Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. Immunity 2:271–279PubMedCrossRefGoogle Scholar
  21. 21.
    Akdis M, Simon HU, Weigl L, Kreyden O, Blaser K, Akdis CA (1999) Skin homing (cutaneous lymphocyte-associated antigen-positive) CD8+ T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis. J Immunol 163:466–475PubMedGoogle Scholar
  22. 22.
    Seneviratne SL, Jones L, King AS, Black A, Powell S, McMichael AJ, Ogg GS (2002) Allergen-specific CD8 (+) T cells and atopic disease. J Clin Invest 110:1283–1291PubMedGoogle Scholar
  23. 23.
    O'Sullivan S, Cormican L, Faul JL, Ichinohe S, Johnston SL, Burke CM, Poulter LW (2001) Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am J Resp Crit Care Med 164:560–564PubMedGoogle Scholar
  24. 24.
    van Rensen ELJ, Sont JK, Evertse CE, Willems LNA, Mauad T, Hiemstra PS, Sterk PJ, AMPUL Study Group (2005) Bronchial CD8 cell infiltrate and lung function decline in asthma. Am J Resp Crit Care Med 172:837–841PubMedCrossRefGoogle Scholar
  25. 25.
    Nazaruk RA, Rochford R, Hobbs MV, Cannon MJ (1998) Functional diversity of the CD8(+) T-cell response to Epstein-Barr virus (EBV): implications for the pathogenesis of EBV-associated lymphoproliferative disorders. Blood 91:3875–3883PubMedGoogle Scholar
  26. 26.
    Seder RA, Boulay JL, Finkelman F, Barbier S, Ben-Sasson SZ, Le Gros G, Paul WE (1992) CD8+ T cells can be primed in vitro to produce IL-4. J Immunol 148:1652–1656PubMedGoogle Scholar
  27. 27.
    Coyle AJ, Erard F, Bertrand C, Walti S, Pircher H, Le Gros G (1995) Virus-specific CD8+ cells can switch to interleukin 5 production and induce airway eosinophilia. J Exp Med 181:1229–1233PubMedCrossRefGoogle Scholar
  28. 28.
    Trinchieri G, Scott P (1994) The role of interleukin 12 in the immune response, disease and therapy. Immunol Today 15:460–463PubMedCrossRefGoogle Scholar
  29. 29.
    Fowler DH, Breglio J, Nagel G, Eckhaus MA, Gress RE (1996) Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol 157:4811–4821PubMedGoogle Scholar
  30. 30.
    Li L, Sad S, Kagi D, Mosmann TR (1997) CD8 Tc1 and Tc2 cells secrete distinct cytokine patterns in vitro and in vivo but induce similar inflammatory reactions. J Immunol 158:4152–4161PubMedGoogle Scholar
  31. 31.
    Ying S, Humbert M, Barkans J, Corrigan CJ, Pfister R, Menz G, Larche M, Robinson DS, Durham SR, Kay AB (1997) Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils, and mast cells in bronchial biopsies obtained from atopic and nonatopic (intrinsic) asthmatics. J Immunol 158:3539–3544PubMedGoogle Scholar
  32. 32.
    Suzuki S, Suzuki Y, Yamamoto N, Matsumoto Y, Shirai A, Okubo T (1998) Influenza A virus infection increases IgE production and airway responsiveness in aerosolized antigen-exposed mice. J Allergy Clin Immunol 102:732–740PubMedCrossRefGoogle Scholar
  33. 33.
    Busse WW (1989) The relationship between viral infections and onset of allergic diseases and asthma. Clin Exp Allergy 19:1–9PubMedCrossRefGoogle Scholar
  34. 34.
    Martinez FD (1995) Viral infections and the development of asthma. Am J Resp Crit Care Med 151:1644–1647PubMedGoogle Scholar
  35. 35.
    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712PubMedCrossRefGoogle Scholar
  36. 36.
    Masopust D, Vezys V, Marzo AL, Lefrancois L (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science 291:2413–2417PubMedCrossRefGoogle Scholar
  37. 37.
    Weninger W, Crowley MA, Manjunath N, von Andrian UH (2001) Migratory properties of naive, effector, and memory CD8(+) T cells. J Exp Med 194:953–966PubMedCrossRefGoogle Scholar
  38. 38.
    Manjunath N, Shankar P, Wan J, Weninger W, Crowley MA, Hieshima K, Springer TA, Fan X, Shen H, Lieberman J, von Andrian UH (2001) Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J Clin Invest 108:871–878PubMedGoogle Scholar
  39. 39.
    Ott VL, Cambier JC, Kappler J, Marrack P, Swanson BJ (2003) Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat Immunol 4:974–981PubMedCrossRefGoogle Scholar
  40. 40.
    Payan DG, Missirian-Bastian A, Goetzl EJ (1984) Human T-lymphocyte subset specificity of the regulatory effects of leukotriene B4. Proc Natl Acad Sci USA 81:3501–3505PubMedCrossRefGoogle Scholar
  41. 41.
    Tager AM, Bromley SK, Medoff BD, Islam SA, Bercury SD, Friedrich EB (2003) Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol 4:982–990PubMedCrossRefGoogle Scholar
  42. 42.
    Ohnishi H, Miyahara N, Swasey CH, Dakhama A, Takeda K, Domenico J, Lucas JJ, Mathis S, Haribabu B, Gelfand EW (2007) Corticosteroids enhance effector memory CD8+ T cell-mediated airway hyperresponsiveness and allergic airway inflammation by upregulating the leukotriene B4 receptor, BLT1. Am J Resp Crit Care Med 175:A255Google Scholar
  43. 43.
    Miyahara N, Takeda K, Miyahara S, Taube C, Joetham A, Koya T, Matsubara S, Dakhama A, Tager AM, Luster AD, Gelfand EW (2005) Leukotriene B4 receptor-1 is essential for allergen- mediated recruitment of CD8+ T cells and airway hyperresponsiveness. J Immunol 174:4979–4984PubMedGoogle Scholar
  44. 44.
    Miyahara N, Takeda K, Miyahara S, Matsubara S, Koya T, Joetham A, Krishnan E, Dakhama A, Haribabu B, Gelfand EW (2005) Requirement for the leukotriene B4 receptor-1 in allergen-induced airway hyperresponsiveness. Am J Resp Crit Care Med 172:161–167PubMedCrossRefGoogle Scholar
  45. 45.
    Taube C, Miyahara N, Ott V, Swanson B, Takeda K, Loader L, Shultz LD, Tager AM, Luster AD, Dakhama A, Gelfand EW (2006) The leukotriene B4 receptor (BLT1) is required for effector CD8+ T cell-mediated, mast cell-dependent airway hyperresponsiveness. J Immunol 176:3157–3164PubMedGoogle Scholar
  46. 46.
    Miyahara N, Miyahara S, Takeda K, Gelfand EW (2006) Role of the LTB4/BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation. Allergol Intl 55:91–97CrossRefGoogle Scholar
  47. 47.
    Gelfand EW, Dakhama A (2006) CD8+ T lymphocytes and leukotriene B4: novel interactions in the persistence and progression of asthma. J Allergy Clin Immunol 117:577–582PubMedCrossRefGoogle Scholar
  48. 48.
    Wenzel SE, Trudeau JB, Kaminsky DA, Cohn J, Martin RJ, Westcott JY (1995) Effect of 5-lipoxygenase inhibition of bronchoconstriction and airway inflammation in nocturnal asthma. Am J Resp Crit Care Med 152:897–905PubMedGoogle Scholar
  49. 49.
    Lukacher A, Braciale V, Braciale T (1984) In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med 160:814–826PubMedCrossRefGoogle Scholar
  50. 50.
    Mueller R, Chanez P, Campbell AM, Bousquet J, Heusser C, Bullock GR (1996) Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis. Resp Med 90:79–85CrossRefGoogle Scholar
  51. 51.
    Olivenstein R, Renzi PM, Yang JP, Rossi P, Laberge S, Waserman S, Martin JG (1993) Depletion of OX-8 lymphocytes from the blood and airways using monoclonal antibodies enhances the late airway response in rats. J Clin Invest 92:1477–1482PubMedCrossRefGoogle Scholar
  52. 52.
    Huang TJ, MacAry PA, Kemeny DM, Chung KF (1999) Effect of CD8+ T-cell depletion on bronchial hyper-responsiveness and inflammation in sensitized and allergen-exposed Brown-Norway rats. Immunology 96:416–423PubMedCrossRefGoogle Scholar
  53. 53.
    Suzuki M, Taha R, Ihaku D, Hamid QA, Martin JG (1999) CD8+ T cells modulate late allergic airway responses in Brown Norway rats. J Immunol 163:5574–5581PubMedGoogle Scholar
  54. 54.
    Isogai S, Rubin A, Maghni K, Ramos-Barbon D, Taha R, Yoshizawa Y, Hamid Q, Martin JG (2003) The effects of CD8+ gammadelta T cells on late allergic airway responses and airway inflammation in rats. J Allergy Clin Immunol 112:547–555PubMedCrossRefGoogle Scholar
  55. 55.
    Isogai S, Jedrzkiewicz S, Taha R, Hamid Q, Martin JG (2005) Resident CD8+ T cells suppress CD4+ T cell-dependent late allergic airway responses. J Allergy Clin Immunol 115:521–526PubMedCrossRefGoogle Scholar
  56. 56.
    Marsland BJ, Harris NL, Camberis M, Kopf M, Hook SM, Le Gros G (2004) Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells. Proc Natl Acad Sci USA 101:6116–6121PubMedCrossRefGoogle Scholar
  57. 57.
    Yeung VP, Gieni RS, Umetsu DT, DeKruyff RH (1998) Heat-killed Listeria monocytogenes as an adjuvant converts established murine Th2-dominated immune responses into Th1-dominated responses. J Immunol 161:4146–4152PubMedGoogle Scholar
  58. 58.
    Hansen G, Yeung VP, Berry G, Umetsu DT, DeKruyff RH (2000) Vaccination with heat-killed Listeria as adjuvant reverses established allergen-induced airway hyperreactivity and inflammation: role of CD8+ T cells and IL-18. J Immunol 164:223–230PubMedGoogle Scholar
  59. 59.
    Stock P, Kallinich T, Akbari O, Quarcoo D, Gerhold K, Wahn U, Umetsu DT, Hamelmann E (2004) CD8(+) T cells regulate immune responses in a murine model of allergen-induced sensitization and airway inflammation. Eur J Immunol 34:1817–1827PubMedCrossRefGoogle Scholar
  60. 60.
    Moore MW, Carbone FR, Bevan MJ (1988) Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell 54:777–785PubMedCrossRefGoogle Scholar
  61. 61.
    Rock KL, Gamble S, Rothstein L (1990) Presentation of exogenous antigen with class I major histocompatibility complex molecules. Science 249:918–921PubMedCrossRefGoogle Scholar
  62. 62.
    McMenamin C, Holt PG (1993) The natural immune response to inhaled soluble protein antigens involves major histocompatibility complex (MHC) class I-restricted CD8+ T cell-mediated but MHC class II-restricted CD4+ T cell-dependent immune deviation resulting in selective suppression of immunoglobulin E production. J Exp Med 178:889–899PubMedCrossRefGoogle Scholar
  63. 63.
    MacAry PA, Holmes BJ, Kemeny DM (1998) Ovalbumin-specific, MHC class I-restricted, β-positive, Tc1 and Tc0 CD8+ T cell clones mediate the in vivo inhibition of rat IgE. J Immunol 160:580–587PubMedGoogle Scholar
  64. 64.
    den Haan JM, Lehar SM, Bevan MJ (2000) CD8(+) but not CD8(−) dendritic cells crossprime cytotoxic T cells in vivo. J Exp Med 192:1685–1696CrossRefGoogle Scholar
  65. 65.
    Schaller MA, Lundy SK, Huffnagle GB, Lukacs NW (2005) CD8+ T cell contributions to allergen induced pulmonary inflammation and airway hyperreactivity. Eur J Immunol 35:2061–2070PubMedCrossRefGoogle Scholar
  66. 66.
    Papadopoulos NG, Stanciu LA, Papi A, Holgate ST, Johnston SL (2002) A defective type I response to rhinovirus in atopic asthma. Thorax 57:328–332PubMedCrossRefGoogle Scholar
  67. 67.
    Coyle AJ, Bertrand C, Tsuyuki S, Pircher H, Walti S, Le Gros G (1996) IL-4 differentiates naive CD8+ T cells to a “Th2-like” phenotype: a link between viral infections and bronchial asthma, Ann NY Acad Sci 796:97–103PubMedCrossRefGoogle Scholar
  68. 68.
    Koya T, Miyahara N, Takeda K, Matsubara S, Matsuda H, Swasey CH, Balhorn A, Dakhama A, Gelfand EW (2007) CD8+ T cell-mediated airway hyperresponsiveness and inflammation is dependent on CD4+ IL-4+ T cells. J Immunol 179:2787–2796PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Nobuaki Miyahara
    • 1
  • Erwin W. Gelfand
    • 2
  1. 1.Division of Cell Biology, Department of PediatricsNational Jewish HealthDenverUSA
  2. 2.Department of Respiratory MedicineOkayama University School of Medicine and DentistryOkayamaJapan

Personalised recommendations