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Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness

Abstract

Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8+ T cells1. Previously, two distinct populations of antigen-experienced CD8+ T cells, termed effector (TEFF) and central memory (TCM) cells, have been described2,3,4,5. After adoptive transfer into CD8-deficient mice, TEFF, but not TCM, cells restored AHR, eosinophilic inflammation and IL-13 levels. TEFF, but not TCM, cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred TEFF cells were a source of IL-13. These data suggest an important role for effector CD8+ T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.

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Figure 1: Reconstitution of lung allergic responses with TEFF and not TCM.
Figure 2: Cytokine levels are restored following transfer of TEFF but not TCM.

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References

  1. Miyahara, N. et al. Contribution of antigen-primed CD8+ T cells in the development of airway hyperresponsiveness and airway inflammation is associated with IL-13. J. Immunol. 172, 2549–2558 (2004).

    Article  CAS  Google Scholar 

  2. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  Google Scholar 

  3. Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).

    Article  CAS  Google Scholar 

  4. Weninger, W., Crowley, M.A., Manjunath, N. & von Andrian, U.H. Migratory properties of naive, effector, and memory CD8+ T cells. J. Exp. Med. 194, 953–966 (2001).

    Article  CAS  Google Scholar 

  5. Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).

    Article  CAS  Google Scholar 

  6. Busse, W.W. & Lemanske Jr., R.F. Asthma. N. Engl. J. Med. 344, 350–362 (2001).

    Article  CAS  Google Scholar 

  7. Oshiba, A. et al. Modulation of antigen-induced B and T cell responses by antigen-specific IgE antibodies. J. Immunol. 159, 4056–4063 (1997).

    CAS  PubMed  Google Scholar 

  8. De Sanctis, G.T. et al. T-lymphocytes regulate genetically determined airway hyperresponsiveness in mice. Nat. Med. 3, 460–462 (1997).

    Article  CAS  Google Scholar 

  9. Robinson, D.S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).

    Article  CAS  Google Scholar 

  10. Gonzalez, M.C. et al. Allergen-induced 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, 600–604 (1987).

    Article  CAS  Google Scholar 

  11. O'Sullivan, S. et al. Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am. J. Resp. Crit. Care Med. 164, 560–564 (2001).

    Article  CAS  Google Scholar 

  12. Hamelmann, E. et al. Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a murine model of airway sensitization. J. Exp. Med. 183, 1719–1729 (1996).

    Article  CAS  Google Scholar 

  13. Swanson, B.J., Murakami, M., Mitchell, T.C., Kappler, J. & Marrack, P. RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process. Immunity 17, 605–615 (2002).

    Article  CAS  Google Scholar 

  14. Ott, V.L., Cambier, J.C., Kappler, J., Marrack, P. & Swanson, B.J. Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat. Immunol. 4, 974–981 (2003).

    Article  CAS  Google Scholar 

  15. Takeda, K. et al. Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice. J. Exp. Med. 186, 449–454 (1997).

    Article  CAS  Google Scholar 

  16. Tomkinson, A. et al. Temporal association between airway hyperresponsiveness and airway eosinophilia in ovalbumin-sensitized mice. Am. J. Respir. Crit. Care Med. 163, 721–730 (2001).

    Article  CAS  Google Scholar 

  17. Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).

    Article  CAS  Google Scholar 

  18. Hoshino, T., Winkler-Pickett, R.T., Mason, A.T., Ortaldo, J.R. & Young, H.A. IL-13 production by NK cells: IL-13-producing NK and T cells are present in vivo in the absence of IFN-γ. J. Immunol. 162, 51–59 (1999).

    CAS  PubMed  Google Scholar 

  19. Akbari, O. et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat. Med. 9, 582–588 (2003).

    Article  CAS  Google Scholar 

  20. Burd, P.R., Thompson W.C., Max, E.E. & Mills, F.C. Activated mast cells produce interleukin 13. J. Exp. Med. 181, 1373–1380 (1995).

    Article  CAS  Google Scholar 

  21. Grunstein, M.M. et al. IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L520–L528 (2002).

    Article  CAS  Google Scholar 

  22. Watanabe, A. et al. Transfer of allergic airway responses with antigen-primed CD4+ but not CD8+ T cells in brown Norway rats. J. Clin. Invest. 96, 1303–1310 (1995).

    Article  CAS  Google Scholar 

  23. Fung-Leung, W.P., Schilham, M.W. & Rahemtulla, A. CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell 65, 443–449 (1991).

    Article  CAS  Google Scholar 

  24. Fabien, N., Bergerot, I., Maguer-Satta, V., Orgiazzi, J. & Thivolet, C. Pancreatic lymph nodes are early targets of T cells during adoptive transfer of diabetes in NOD mice. J. Autoimmun. 8, 323–334 (1995).

    Article  CAS  Google Scholar 

  25. Oshiba, A. et al. Passive transfer of immediate hypersensitivity and airway hyperresponsiveness by allergen-specific immunoglobulin (Ig) E and IgG1 in mice. J. Clin. Invest. 97, 1398–1408 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Cambier, P. Marrack and J. Kappler for support; J.J. Lee for the antibody to major basic protein; and L.N. Cunningham and D. Nabighian for assistance. This work was supported by National Institute of Health grants HL-36577, HL-61005 and AI-42246 and Environmental Protection Agency grants R825702 (E.W.G.) and AI-52225.

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Correspondence to Erwin W Gelfand.

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Supplementary information

Supplementary Fig. 1

Preferential treatment of TEFF in the lung (PDF 153 kb)

Supplementary Fig. 2

Quantitation of TEFF or TCM in the lung sections from the submucosal tissue around the major airways or peripheral tissue. (PDF 20 kb)

Supplementary Fig. 3

Histograms of CFSE-labeled TEFF and TCM prior to transfer and following recovery from the lungs and PBLN, respectively, of sensitized and challenged CD8-deficient mice. (PDF 23 kb)

Supplementary Fig. 4

Intracellular staining for IL-4, IL-5, IL-13, and IFN-γ in CD8+ T cells from OVA sensitized and challenged recipient CD8-deficient mice following transfer of TCM. (PDF 22 kb)

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Miyahara, N., Swanson, B., Takeda, K. et al. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat Med 10, 865–869 (2004). https://doi.org/10.1038/nm1081

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