Abstract
CD8(+) T cells infiltrate the lung in many clinical conditions, particularly in interstitial lung disease. The role(s) that CD8(+) T cells might be playing in the pathogenesis of inflammatory lung disease is unclear at present, as is the direct contribution of CD8(+) T cell effector activities to lung injury. This report describes a transgenic model used to evaluate the impact, on respiratory structure and function, of CD8(+) T lymphocyte recognition of a target antigen expressed endogenously in alveolar epithelial cells. We found that adoptive transfer of cloned CD8(+) cytotoxic T lymphocytes (CTLs) specific for an alveolar neo-antigen (influenza hemagglutinin) leads to progressive lethal injury in transgenic mice, which dramatically affects lung structure and function. Transgenic recipients of CD8(+) CTLs exhibited tachypnea and progressive weight loss, becoming moribund over a period of several days. Concomitantly, the animals developed a progressive interstitial pneumonitis characterized initially by lymphocytic infiltration of alveolar walls and spaces, followed by an exuberant mononuclear cell infiltration that correlated with restrictive pulmonary mechanics and a progressive diffusion impairment. These results indicate that antigen-specific CD8(+) T cell recognition of an alveolar epithelial "autoantigen" is, in and of itself, sufficient to trigger an inflammatory cascade that results in the histological and physiological manifestations of interstitial pneumonia.
Full Text
The Full Text of this article is available as a PDF (554.4 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ada G. L., Jones P. D. The immune response to influenza infection. Curr Top Microbiol Immunol. 1986;128:1–54. doi: 10.1007/978-3-642-71272-2_1. [DOI] [PubMed] [Google Scholar]
- Agustí A. G., Roca J., Gea J., Wagner P. D., Xaubet A., Rodriguez-Roisin R. Mechanisms of gas-exchange impairment in idiopathic pulmonary fibrosis. Am Rev Respir Dis. 1991 Feb;143(2):219–225. doi: 10.1164/ajrccm/143.2.219. [DOI] [PubMed] [Google Scholar]
- Alwan W. H., Kozlowska W. J., Openshaw P. J. Distinct types of lung disease caused by functional subsets of antiviral T cells. J Exp Med. 1994 Jan 1;179(1):81–89. doi: 10.1084/jem.179.1.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bergmann K. C., Lachmann B., Noack K. Lung mechanics in orally immunized mice after aerolized exposure to influenza virus. Respiration. 1984;46(2):218–221. doi: 10.1159/000194692. [DOI] [PubMed] [Google Scholar]
- Bowden D. H. Unraveling pulmonary fibrosis: the bleomycin model. Lab Invest. 1984 May;50(5):487–488. [PubMed] [Google Scholar]
- Cao W., Tykodi S. S., Esser M. T., Braciale V. L., Braciale T. J. Partial activation of CD8+ T cells by a self-derived peptide. Nature. 1995 Nov 16;378(6554):295–298. doi: 10.1038/378295a0. [DOI] [PubMed] [Google Scholar]
- Costabel U., Teschler H., Guzman J. Bronchiolitis obliterans organizing pneumonia (BOOP): the cytological and immunocytological profile of bronchoalveolar lavage. Eur Respir J. 1992 Jul;5(7):791–797. [PubMed] [Google Scholar]
- Crystal R. G., Fulmer J. D., Roberts W. C., Moss M. L., Line B. R., Reynolds H. Y. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med. 1976 Dec;85(6):769–788. doi: 10.7326/0003-4819-85-6-769. [DOI] [PubMed] [Google Scholar]
- Curtis J. L., Warnock M. L., Arraj S. M., Kaltreider H. B. Histologic analysis of an immune response in the lung parenchyma of mice. Angiopathy accompanies inflammatory cell influx. Am J Pathol. 1990 Sep;137(3):689–699. [PMC free article] [PubMed] [Google Scholar]
- Depledge M. H., Collis C. H., Barrett A. A technique for measuring carbon monoxide uptake in mice. Int J Radiat Oncol Biol Phys. 1981 Apr;7(4):485–489. doi: 10.1016/0360-3016(81)90134-6. [DOI] [PubMed] [Google Scholar]
- Doherty D. E., Downey G. P., Schwab B., 3rd, Elson E., Worthen G. S. Lipolysaccharide-induced monocyte retention in the lung. Role of monocyte stiffness, actin assembly, and CD18-dependent adherence. J Immunol. 1994 Jul 1;153(1):241–255. [PubMed] [Google Scholar]
- Eklund A., Broman L., Broman M., Holmgren A. V/Q and alveolar gas exchange in pulmonary sarcoidosis. Eur Respir J. 1989 Feb;2(2):135–144. [PubMed] [Google Scholar]
- Enelow R. I., Stoler M. H., Srikiatkhachorn A., Kerlakian C., Agersborg S., Whitsett J. A., Braciale T. J. A lung-specific neo-antigen elicits specific CD8+ T cell tolerance with preserved CD4+ T cell reactivity. Implications for immune-mediated lung disease. J Clin Invest. 1996 Aug 15;98(4):914–922. doi: 10.1172/JCI118874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fulcher D. A., Lyons A. B., Korn S. L., Cook M. C., Koleda C., Parish C., Fazekas de St Groth B., Basten A. The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help. J Exp Med. 1996 May 1;183(5):2313–2328. doi: 10.1084/jem.183.5.2313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Graham M. B., Braciale V. L., Braciale T. J. Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med. 1994 Oct 1;180(4):1273–1282. doi: 10.1084/jem.180.4.1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Graham MB, Braciale TJ, Braciale VL. Use of Antiviral T-Lymphocyte Clones to Characterize Antigen Presentation and T-Lymphocyte Subsets. Methods. 1996 Jun;9(3):439–444. doi: 10.1006/meth.1996.0050. [DOI] [PubMed] [Google Scholar]
- Hartsfield C. L., Lipke D., Lai Y. L., Cohen D. A., Gillespie M. N. Pulmonary mechanical and immunologic dysfunction in a murine model of AIDS. Am J Physiol. 1997 Apr;272(4 Pt 1):L699–L706. doi: 10.1152/ajplung.1997.272.4.L699. [DOI] [PubMed] [Google Scholar]
- Hempleman S. C., Hughes J. M. Estimating exercise DLO2 and diffusion limitation in patients with interstitial fibrosis. Respir Physiol. 1991 Feb;83(2):167–178. doi: 10.1016/0034-5687(91)90026-f. [DOI] [PubMed] [Google Scholar]
- Hu H., Stein-Streilein J. Hapten-immune pulmonary interstitial fibrosis (HIPIF) in mice requires both CD4+ and CD8+ T lymphocytes. J Leukoc Biol. 1993 Nov;54(5):414–422. doi: 10.1002/jlb.54.5.414. [DOI] [PubMed] [Google Scholar]
- Kojima H., Shinohara N., Hanaoka S., Someya-Shirota Y., Takagaki Y., Ohno H., Saito T., Katayama T., Yagita H., Okumura K. Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. Immunity. 1994 Aug;1(5):357–364. doi: 10.1016/1074-7613(94)90066-3. [DOI] [PubMed] [Google Scholar]
- Kradin R. L., Divertie M. B., Colvin R. B., Ramirez J., Ryu J., Carpenter H. A., Bhan A. K. Usual interstitial pneumonitis is a T-cell alveolitis. Clin Immunol Immunopathol. 1986 Aug;40(2):224–235. doi: 10.1016/0090-1229(86)90025-5. [DOI] [PubMed] [Google Scholar]
- Kägi D., Vignaux F., Ledermann B., Bürki K., Depraetere V., Nagata S., Hengartner H., Golstein P. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science. 1994 Jul 22;265(5171):528–530. doi: 10.1126/science.7518614. [DOI] [PubMed] [Google Scholar]
- Leatherman J. W., Michael A. F., Schwartz B. A., Hoidal J. R. Lung T cells in hypersensitivity pneumonitis. Ann Intern Med. 1984 Mar;100(3):390–392. doi: 10.7326/0003-4819-100-3-390. [DOI] [PubMed] [Google Scholar]
- Leturcq D. J., Moriarty A. M., Talbott G., Winn R. K., Martin T. R., Ulevitch R. J. Antibodies against CD14 protect primates from endotoxin-induced shock. J Clin Invest. 1996 Oct 1;98(7):1533–1538. doi: 10.1172/JCI118945. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lukacher A. E., Braciale V. L., Braciale T. J. In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med. 1984 Sep 1;160(3):814–826. doi: 10.1084/jem.160.3.814. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lyons A. B., Parish C. R. Determination of lymphocyte division by flow cytometry. J Immunol Methods. 1994 May 2;171(1):131–137. doi: 10.1016/0022-1759(94)90236-4. [DOI] [PubMed] [Google Scholar]
- Openshaw P. J. Immunity and immunopathology to respiratory syncytial virus. The mouse model. Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 2):S59–S62. doi: 10.1164/ajrccm/152.4_Pt_2.S59. [DOI] [PubMed] [Google Scholar]
- Ryan S. F., Barrett C. R., Lavietes M. H., Bell A. L., Rochester D. F. Volume-pressure and morphometric observations after acute alveolar injury in the dog from N-nitroso-N-methylurethane. Am Rev Respir Dis. 1978 Oct;118(4):735–745. doi: 10.1164/arrd.1978.118.4.735. [DOI] [PubMed] [Google Scholar]
- Sabo J. P., Kimmel E. C., Diamond L. Effects of the Clara cell toxin, 4-ipomeanol, on pulmonary function in rats. J Appl Physiol Respir Environ Exerc Physiol. 1983 Feb;54(2):337–344. doi: 10.1152/jappl.1983.54.2.337. [DOI] [PubMed] [Google Scholar]
- Scherle P. A., Palladino G., Gerhard W. Mice can recover from pulmonary influenza virus infection in the absence of class I-restricted cytotoxic T cells. J Immunol. 1992 Jan 1;148(1):212–217. [PubMed] [Google Scholar]
- Schrier D. J., Phan S. H., Ward P. A. Cellular sensitivity to collagen in bleomycin-treated rats. J Immunol. 1982 Nov;129(5):2156–2159. [PubMed] [Google Scholar]
- Shanley T. P., Schmal H., Friedl H. P., Jones M. L., Ward P. A. Role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in acute lung injury in rats. J Immunol. 1995 May 1;154(9):4793–4802. [PubMed] [Google Scholar]
- Snider G. L., Hayes J. A., Korthy A. L. Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin: pathology and stereology. Am Rev Respir Dis. 1978 Jun;117(6):1099–1108. doi: 10.1164/arrd.1978.117.6.1099. [DOI] [PubMed] [Google Scholar]
- Stein-Streilein J., Lipscomb M. F., Hart D. A., Darden A. Graft-versus-host reaction in the lung. Transplantation. 1981 Jul;32(1):38–44. doi: 10.1097/00007890-198107000-00008. [DOI] [PubMed] [Google Scholar]
- Takezawa J., Miller F. J., O'Neil J. J. Single-breath diffusing capacity and lung volumes in small laboratory mammals. J Appl Physiol Respir Environ Exerc Physiol. 1980 Jun;48(6):1052–1059. doi: 10.1152/jappl.1980.48.6.1052. [DOI] [PubMed] [Google Scholar]
- Walsh C. M., Glass A. A., Chiu V., Clark W. R. The role of the Fas lytic pathway in a perforin-less CTL hybridoma. J Immunol. 1994 Sep 15;153(6):2506–2514. [PubMed] [Google Scholar]
- Walsh C. M., Matloubian M., Liu C. C., Ueda R., Kurahara C. G., Christensen J. L., Huang M. T., Young J. D., Ahmed R., Clark W. R. Immune function in mice lacking the perforin gene. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10854–10858. doi: 10.1073/pnas.91.23.10854. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wells M. A., Albrecht P., Ennis F. A. Recovery from a viral respiratory infection. I. Influenza pneumonia in normal and T-deficient mice. J Immunol. 1981 Mar;126(3):1036–1041. [PubMed] [Google Scholar]