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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).
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).
Manjunath, N. et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Invest. 108, 871–878 (2001).
Busse, W.W. & Lemanske Jr., R.F. Asthma. N. Engl. J. Med. 344, 350–362 (2001).
Oshiba, A. et al. Modulation of antigen-induced B and T cell responses by antigen-specific IgE antibodies. J. Immunol. 159, 4056–4063 (1997).
De Sanctis, G.T. et al. T-lymphocytes regulate genetically determined airway hyperresponsiveness in mice. Nat. Med. 3, 460–462 (1997).
Robinson, D.S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).
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).
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).
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).
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).
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).
Takeda, K. et al. Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice. J. Exp. Med. 186, 449–454 (1997).
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).
Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).
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).
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).
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).
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).
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).
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).
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).
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).
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.
The authors declare no competing financial interests.
Preferential treatment of TEFF in the lung (PDF 153 kb)
Quantitation of TEFF or TCM in the lung sections from the submucosal tissue around the major airways or peripheral tissue. (PDF 20 kb)
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)
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)
About this article
Cite this article
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
European Respiratory Review (2019)
The Ethanol Extract of Holotrichia diomphalia Larvae, Containing Fatty acids and Amino acids, Exerts Anti-Asthmatic Effects through Inhibition of the GATA-3/Th2 Signaling Pathway in Asthmatic Mice
Journal of Cellular Physiology (2019)
Hypoxia enhances CD8+ TC2 cell–dependent airway hyperresponsiveness and inflammation through hypoxia-inducible factor 1α
Journal of Allergy and Clinical Immunology (2019)
Increased IL-4- and IL-17-producing CD8+ cells are related to decreased CD39+CD4+Foxp3+ cells in allergic asthma
Journal of Asthma (2018)