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. 1996 Aug;64(8):3201–3209. doi: 10.1128/iai.64.8.3201-3209.1996

Naturally acquired Pneumocystis carinii pneumonia in gene disruption mutant mice: roles of distinct T-cell populations in infection.

R Hanano 1, K Reifenberg 1, S H Kaufmann 1
PMCID: PMC174208  PMID: 8757854

Abstract

When kept under strict specific-pathogen-free conditions, H-21-Abeta (Abeta(-/-),T-cell receptor beta (TCRbeta(-/-)), and recombinase-activating gene 1 (RAG-1(-/-) gene disruption mutant mice, deficient in conventional CD4+ T cells, TCRalphabeta cells, and all peripheral T and B lymphocytes, respectively, consistently developed lethal Pneumocystis carinii pneumonia through natural infection. The most severe symptoms appeared in RAG-1(-/-) mutants. In contrast, TCRdelta(-/-) and beta2-microglobulin(-/-)(beta2m-/-) mutants, deficient in TCRgammadelta cells and conventional CD8alphabeta+ TCRalphabeta cells, respectively, were fully resistant to infection. Our data indicate not only the insufficiency but also the dispensability of CD8 alphabeta+TCRalphabeta cells and of TCRgammadelta lymphocytes in resistance to P. carinii infection. Under disease conditions, large numbers of unusual single-positive CD4+ and CD8alphabeta+ as well as double-negative TCRgammadelta subpopulations of cells accumulated in lungs of TCRbeta(-/-) mutants. This accumulation was consistently accompanied by a drastic increase in the pulmonary B-cell population. In contrast, CD8alphabeta+ TCR alpha beta cells, but no B cells, appeared in lungs of parasitized Abeta (-/-) mutants. Since lung damage and parasite numbers were less prominent in morbid TCRbeta(-/-) and Abeta(-/-) mutants than in diseased RAG-1(-/-) mice, the remaining lymphocytes accumulating in lungs of the former two mutants seem to perform residual resistance functions.

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Selected References

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  1. Bartlett M. S., Fishman J. A., Queener S. F., Durkin M. M., Jay M. A., Smith J. W. New rat model of Pneumocystis carinii infection. J Clin Microbiol. 1988 Jun;26(6):1100–1102. doi: 10.1128/jcm.26.6.1100-1102.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ceredig R., Medveczky J., Skulimowski A. Mouse fetal thymus lobes cultured in IL-2 generate CD3+, TCR-gamma delta-expressing CD4-/CD8+ and CD4-/CD8- cells. J Immunol. 1989 May 15;142(10):3353–3360. [PubMed] [Google Scholar]
  3. Cosgrove D., Gray D., Dierich A., Kaufman J., Lemeur M., Benoist C., Mathis D. Mice lacking MHC class II molecules. Cell. 1991 Sep 6;66(5):1051–1066. doi: 10.1016/0092-8674(91)90448-8. [DOI] [PubMed] [Google Scholar]
  4. Cron R. Q., Gajewski T. F., Sharrow S. O., Fitch F. W., Matis L. A., Bluestone J. A. Phenotypic and functional analysis of murine CD3+,CD4-,CD8- TCR-gamma delta-expressing peripheral T cells. J Immunol. 1989 Jun 1;142(11):3754–3762. [PubMed] [Google Scholar]
  5. Cushion M. T., Stringer J. R., Walzer P. D. Cellular and molecular biology of Pneumocystis carinii. Int Rev Cytol. 1991;131:59–107. doi: 10.1016/s0074-7696(08)62017-3. [DOI] [PubMed] [Google Scholar]
  6. Ezekowitz R. A., Williams D. J., Koziel H., Armstrong M. Y., Warner A., Richards F. F., Rose R. M. Uptake of Pneumocystis carinii mediated by the macrophage mannose receptor. Nature. 1991 May 9;351(6322):155–158. doi: 10.1038/351155a0. [DOI] [PubMed] [Google Scholar]
  7. Fisher A. G., Ceredig R. Gamma delta T cells expressing CD8 or CD4low appear early in murine foetal thymus development. Int Immunol. 1991 Dec;3(12):1323–1328. doi: 10.1093/intimm/3.12.1323. [DOI] [PubMed] [Google Scholar]
  8. Goodman T., Lefrancois L. Intraepithelial lymphocytes. Anatomical site, not T cell receptor form, dictates phenotype and function. J Exp Med. 1989 Nov 1;170(5):1569–1581. doi: 10.1084/jem.170.5.1569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goodman T., Lefrançois L. Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature. 1988 Jun 30;333(6176):855–858. doi: 10.1038/333855a0. [DOI] [PubMed] [Google Scholar]
  10. Gradus M. S., Ivey M. H. An improved method of isolating Pneumocystis carinii from infected rat lungs. J Parasitol. 1986 Oct;72(5):690–698. [PubMed] [Google Scholar]
  11. Harmsen A. G., Chen W. Resolution of Pneumocystis carinii pneumonia in CD4+ lymphocyte-depleted mice given aerosols of heat-treated Escherichia coli. J Exp Med. 1992 Sep 1;176(3):881–886. doi: 10.1084/jem.176.3.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Harmsen A. G., Stankiewicz M. Requirement for CD4+ cells in resistance to Pneumocystis carinii pneumonia in mice. J Exp Med. 1990 Sep 1;172(3):937–945. doi: 10.1084/jem.172.3.937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hughes W. T. Animal models for Pneumocystis carinii pneumonia. J Protozool. 1989 Jan-Feb;36(1):41–45. doi: 10.1111/j.1550-7408.1989.tb02688.x. [DOI] [PubMed] [Google Scholar]
  14. Hughes W. T. Natural mode of acquisition for de novo infection with Pneumocystis carinii. J Infect Dis. 1982 Jun;145(6):842–848. doi: 10.1093/infdis/145.6.842. [DOI] [PubMed] [Google Scholar]
  15. Itohara S., Mombaerts P., Lafaille J., Iacomini J., Nelson A., Clarke A. R., Hooper M. L., Farr A., Tonegawa S. T cell receptor delta gene mutant mice: independent generation of alpha beta T cells and programmed rearrangements of gamma delta TCR genes. Cell. 1993 Feb 12;72(3):337–348. doi: 10.1016/0092-8674(93)90112-4. [DOI] [PubMed] [Google Scholar]
  16. Koziel H., O'Riordan D., Warner A., Rose R. M. Alveolar macrophage interaction with Pneumocystis carinii. Immunol Ser. 1994;60:417–436. [PubMed] [Google Scholar]
  17. Ladel C. H., Daugelat S., Kaufmann S. H. Immune response to Mycobacterium bovis bacille Calmette Guérin infection in major histocompatibility complex class I- and II-deficient knock-out mice: contribution of CD4 and CD8 T cells to acquired resistance. Eur J Immunol. 1995 Feb;25(2):377–384. doi: 10.1002/eji.1830250211. [DOI] [PubMed] [Google Scholar]
  18. Lagoo A. S., Eldridge J. H., Lagoo-Deenadaylan S., Black C. A., Ridwan B. U., Hardy K. J., McGhee J. R., Beagley K. W. Peyer's patch CD8+ memory T cells secrete T helper type 1 and type 2 cytokines and provide help for immunoglobulin secretion. Eur J Immunol. 1994 Dec;24(12):3087–3092. doi: 10.1002/eji.1830241226. [DOI] [PubMed] [Google Scholar]
  19. Lanken P. N., Minda M., Pietra G. G., Fishman A. P. Alveolar response to experimental Pneumocystis carinii pneumonia in the rat. Am J Pathol. 1980 Jun;99(3):561–588. [PMC free article] [PubMed] [Google Scholar]
  20. Lefrançois L., Puddington L. Extrathymic intestinal T-cell development: virtual reality? Immunol Today. 1995 Jan;16(1):16–21. doi: 10.1016/0167-5699(95)80065-4. [DOI] [PubMed] [Google Scholar]
  21. MacDonald H. R., Schreyer M., Howe R. C., Bron C. Selective expression of CD8 alpha (Ly-2) subunit on activated thymic gamma/delta cells. Eur J Immunol. 1990 Apr;20(4):927–930. doi: 10.1002/eji.1830200431. [DOI] [PubMed] [Google Scholar]
  22. Matsumoto Y., Frenkel J. K., Aikawa M., Yoshida Y. Proliferation of Pneumocystis trophozoites in human lymph nodes and in nude mice lungs. J Protozool. 1989 Jan-Feb;36(1):33S–34S. doi: 10.1111/j.1550-7408.1989.tb02682.x. [DOI] [PubMed] [Google Scholar]
  23. Miller R. F., Mitchell D. M. AIDS and the lung: update 1995. 1. Pneumocystis carinii pneumonia. Thorax. 1995 Feb;50(2):191–200. doi: 10.1136/thx.50.2.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mombaerts P., Arnoldi J., Russ F., Tonegawa S., Kaufmann S. H. Different roles of alpha beta and gamma delta T cells in immunity against an intracellular bacterial pathogen. Nature. 1993 Sep 2;365(6441):53–56. doi: 10.1038/365053a0. [DOI] [PubMed] [Google Scholar]
  25. Mombaerts P., Clarke A. R., Hooper M. L., Tonegawa S. Creation of a large genomic deletion at the T-cell antigen receptor beta-subunit locus in mouse embryonic stem cells by gene targeting. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3084–3087. doi: 10.1073/pnas.88.8.3084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  27. Poussier P., Julius M. Thymus independent T cell development and selection in the intestinal epithelium. Annu Rev Immunol. 1994;12:521–553. doi: 10.1146/annurev.iy.12.040194.002513. [DOI] [PubMed] [Google Scholar]
  28. Ramsdell F., Seaman M. S., Clifford K. N., Fanslow W. C. CD40 ligand acts as a costimulatory signal for neonatal thymic gamma delta T cells. J Immunol. 1994 Mar 1;152(5):2190–2197. [PubMed] [Google Scholar]
  29. Roths J. B., Sidman C. L. Both immunity and hyperresponsiveness to Pneumocystis carinii result from transfer of CD4+ but not CD8+ T cells into severe combined immunodeficiency mice. J Clin Invest. 1992 Aug;90(2):673–678. doi: 10.1172/JCI115910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Seder R. A., Le Gros G. G. The functional role of CD8+ T helper type 2 cells. J Exp Med. 1995 Jan 1;181(1):5–7. doi: 10.1084/jem.181.1.5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Shellito J., Suzara V. V., Blumenfeld W., Beck J. M., Steger H. J., Ermak T. H. A new model of Pneumocystis carinii infection in mice selectively depleted of helper T lymphocytes. J Clin Invest. 1990 May;85(5):1686–1693. doi: 10.1172/JCI114621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sukura A., Konttinen Y. T., Sepper R., Kaartinen L., Sorsa T., Lindberg L. A. Collagenases and the serine proteinases elastase and cathepsin G in steroid-induced Pneumocystis carinii pneumonia. J Clin Microbiol. 1995 Apr;33(4):829–834. doi: 10.1128/jcm.33.4.829-834.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Theus S. A., Andrews R. P., Steele P., Walzer P. D. Adoptive transfer of lymphocytes sensitized to the major surface glycoprotein of Pneumocystis carinii confers protection in the rat. J Clin Invest. 1995 Jun;95(6):2587–2593. doi: 10.1172/JCI117960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Viney J. L., Dianda L., Roberts S. J., Wen L., Mallick C. A., Hayday A. C., Owen M. J. Lymphocyte proliferation in mice congenitally deficient in T-cell receptor alpha beta + cells. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11948–11952. doi: 10.1073/pnas.91.25.11948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wakefield A. E. Detection of DNA sequences identical to Pneumocystis carinii in samples of ambient air. J Eukaryot Microbiol. 1994 Sep-Oct;41(5):116S–116S. [PubMed] [Google Scholar]
  36. Wakefield A. E., Pixley F. J., Banerji S., Sinclair K., Miller R. F., Moxon E. R., Hopkin J. M. Detection of Pneumocystis carinii with DNA amplification. Lancet. 1990 Aug 25;336(8713):451–453. doi: 10.1016/0140-6736(90)92008-6. [DOI] [PubMed] [Google Scholar]
  37. Walzer P. D. Attachment of microbes to host cells: relevance of Pneumocystis carinii. Lab Invest. 1986 Jun;54(6):589–592. [PubMed] [Google Scholar]
  38. Walzer P. D. Immunopathogenesis of Pneumocystis carinii infection. J Lab Clin Med. 1991 Sep;118(3):206–216. [PubMed] [Google Scholar]
  39. Walzer P. D., Kim C. K., Linke M. J., Pogue C. L., Huerkamp M. J., Chrisp C. E., Lerro A. V., Wixson S. K., Hall E., Shultz L. D. Outbreaks of Pneumocystis carinii pneumonia in colonies of immunodeficient mice. Infect Immun. 1989 Jan;57(1):62–70. doi: 10.1128/iai.57.1.62-70.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Walzer P. D., Schnelle V., Armstrong D., Rosen P. P. Nude mouse: a new experimental model for Pneumocystis carinii infection. Science. 1977 Jul 8;197(4299):177–179. doi: 10.1126/science.301657. [DOI] [PubMed] [Google Scholar]
  41. Wucherpfennig K. W., Liao Y. J., Prendergast M., Prendergast J., Hafler D. A., Strominger J. L. Human fetal liver gamma/delta T cells predominantly use unusual rearrangements of the T cell receptor delta and gamma loci expressed on both CD4+CD8- and CD4-CD8- gamma/delta T cells. J Exp Med. 1993 Feb 1;177(2):425–432. doi: 10.1084/jem.177.2.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yoneda K., Walzer P. D. Mechanism of pulmonary alveolar injury in experimental Pneumocystis carinii pneumonia in the rat. Br J Exp Pathol. 1981 Aug;62(4):339–346. [PMC free article] [PubMed] [Google Scholar]
  43. Zijlstra M., Bix M., Simister N. E., Loring J. M., Raulet D. H., Jaenisch R. Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature. 1990 Apr 19;344(6268):742–746. doi: 10.1038/344742a0. [DOI] [PubMed] [Google Scholar]

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