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. 1994 Jun;82(2):255–260.

Cutaneous leishmaniasis: co-ordinate expression of granzyme A and lymphokines by CD4+ T cells from susceptible mice.

S Frischholz 1, M Röllinghoff 1, H Moll 1
PMCID: PMC1414810  PMID: 7927497

Abstract

We have recently demonstrated that the frequency of T cells expressing granzyme A is significantly higher in skin lesions and spleens of susceptible BALB/c mice compared with resistant C57BL/6 mice infected with Leishmania major, a cause of human cutaneous leishmaniasis. In the present study, we have performed in vitro studies to characterize the subpopulation, the antigen responsiveness and the lymphokine production pattern of granzyme A-expressing T cells in L. major-infected mice. Using a limiting dilution system for functional analysis of selected T cells at the clonal level, we could show that granzyme A activity in infected BALB/c mice can be assigned to L. major-reactive CD4+ T cells secreting interleukin-2 (IL-2) and IL-4. Granzyme A production was most pronounced in the early phase of infection. On the other hand, granzyme A expression could not be detected in C57BL/6-derived T cells responding to L. major. The data support the suggestion that granzyme A is produced by L. major-responsive CD4+ T cells facilitating lesion formation and the dissemination of infection.

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Selected References

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  1. Belosevic M., Finbloom D. S., Van Der Meide P. H., Slayter M. V., Nacy C. A. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989 Jul 1;143(1):266–274. [PubMed] [Google Scholar]
  2. Bogdan C., Gessner A., Röllinghoff M. Cytokines in leishmaniasis: a complex network of stimulatory and inhibitory interactions. Immunobiology. 1993 Nov;189(3-4):356–396. doi: 10.1016/S0171-2985(11)80366-9. [DOI] [PubMed] [Google Scholar]
  3. Brunner G., Simon M. M., Kramer M. D. Activation of pro-urokinase by the human T cell-associated serine proteinase HuTSP-1. FEBS Lett. 1990 Jan 15;260(1):141–144. doi: 10.1016/0014-5793(90)80087-y. [DOI] [PubMed] [Google Scholar]
  4. Cobbold S. P., Jayasuriya A., Nash A., Prospero T. D., Waldmann H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature. 1984 Dec 6;312(5994):548–551. doi: 10.1038/312548a0. [DOI] [PubMed] [Google Scholar]
  5. Ebnet K., Chluba-de Tapia J., Hurtenbach U., Kramer M. D., Simon M. M. In vivo primed mouse T cells selectively express T cell-specific serine proteinase-1 and the proteinase-like molecules granzyme B and C. Int Immunol. 1991 Jan;3(1):9–19. doi: 10.1093/intimm/3.1.9. [DOI] [PubMed] [Google Scholar]
  6. Fruth U., Nerz G., Prester M., Simon H. G., Kramer M. D., Simon M. M. Determination of frequency of T cells expressing the T cell-specific serine proteinase 1 (TSP-1) reveals two types of L3T4+ T lymphocytes. Eur J Immunol. 1988 May;18(5):773–781. doi: 10.1002/eji.1830180518. [DOI] [PubMed] [Google Scholar]
  7. Fruth U., Prester M., Golecki J. R., Hengartner H., Simon H. G., Kramer M. D., Simon M. M. The T cell-specific serine proteinase TSP-1 is associated with cytoplasmic granules of cytolytic T lymphocytes. Eur J Immunol. 1987 May;17(5):613–621. doi: 10.1002/eji.1830170506. [DOI] [PubMed] [Google Scholar]
  8. Gershenfeld H. K., Weissman I. L. Cloning of a cDNA for a T cell-specific serine protease from a cytotoxic T lymphocyte. Science. 1986 May 16;232(4752):854–858. doi: 10.1126/science.2422755. [DOI] [PubMed] [Google Scholar]
  9. Griffiths G. M., Mueller C. Expression of perforin and granzymes in vivo: potential diagnostic markers for activated cytotoxic cells. Immunol Today. 1991 Nov;12(11):415–419. doi: 10.1016/0167-5699(91)90145-J. [DOI] [PubMed] [Google Scholar]
  10. Heinzel F. P., Sadick M. D., Holaday B. J., Coffman R. L., Locksley R. M. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med. 1989 Jan 1;169(1):59–72. doi: 10.1084/jem.169.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Heinzel F. P., Sadick M. D., Mutha S. S., Locksley R. M. Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7011–7015. doi: 10.1073/pnas.88.16.7011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kramer M. D., Binninger L., Schirrmacher V., Moll H., Prester M., Nerz G., Simon M. M. Characterization and isolation of a trypsin-like serine protease from a long-term culture cytolytic T cell line and its expression by functionally distinct T cells. J Immunol. 1986 Jun 15;136(12):4644–4651. [PubMed] [Google Scholar]
  14. Kramer M. D., Fruth U., Simon H. G., Simon M. M. Expression of cytoplasmic granules with T cell-associated serine proteinase-1 activity in Ly-2+(CD8+) T lymphocytes responding to lymphocytic choriomeningitis virus in vivo. Eur J Immunol. 1989 Jan;19(1):151–156. doi: 10.1002/eji.1830190124. [DOI] [PubMed] [Google Scholar]
  15. Liew F. Y., O'Donnell C. A. Immunology of leishmaniasis. Adv Parasitol. 1993;32:161–259. doi: 10.1016/s0065-308x(08)60208-0. [DOI] [PubMed] [Google Scholar]
  16. Locksley R. M., Louis J. A. Immunology of leishmaniasis. Curr Opin Immunol. 1992 Aug;4(4):413–418. doi: 10.1016/s0952-7915(06)80032-4. [DOI] [PubMed] [Google Scholar]
  17. Masson D., Nabholz M., Estrade C., Tschopp J. Granules of cytolytic T-lymphocytes contain two serine esterases. EMBO J. 1986 Jul;5(7):1595–1600. doi: 10.1002/j.1460-2075.1986.tb04401.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Moll H., Müller C., Gillitzer R., Fuchs H., Röllinghoff M., Simon M. M., Kramer M. D. Expression of T-cell-associated serine proteinase 1 during murine Leishmania major infection correlates with susceptibility to disease. Infect Immun. 1991 Dec;59(12):4701–4705. doi: 10.1128/iai.59.12.4701-4705.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moll H., Röllinghoff M. Resistance to murine cutaneous leishmaniasis is mediated by TH1 cells, but disease-promoting CD4+ cells are different from TH2 cells. Eur J Immunol. 1990 Sep;20(9):2067–2074. doi: 10.1002/eji.1830200927. [DOI] [PubMed] [Google Scholar]
  20. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  21. Mueller C., Gershenfeld H. K., Lobe C. G., Okada C. Y., Bleackley R. C., Weissman I. L. A high proportion of T lymphocytes that infiltrate H-2-incompatible heart allografts in vivo express genes encoding cytotoxic cell-specific serine proteases, but do not express the MEL-14-defined lymph node homing receptor. J Exp Med. 1988 Mar 1;167(3):1124–1136. doi: 10.1084/jem.167.3.1124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Müller C., Kägi D., Aebischer T., Odermatt B., Held W., Podack E. R., Zinkernagel R. M., Hengartner H. Detection of perforin and granzyme A mRNA in infiltrating cells during infection of mice with lymphocytic choriomeningitis virus. Eur J Immunol. 1989 Jul;19(7):1253–1259. doi: 10.1002/eji.1830190716. [DOI] [PubMed] [Google Scholar]
  23. Nacy C. A., Meltzer M. S. T-cell-mediated activation of macrophages. Curr Opin Immunol. 1991 Jun;3(3):330–335. doi: 10.1016/0952-7915(91)90033-w. [DOI] [PubMed] [Google Scholar]
  24. Ohara J., Paul W. E. Production of a monoclonal antibody to and molecular characterization of B-cell stimulatory factor-1. Nature. 1985 May 23;315(6017):333–336. doi: 10.1038/315333a0. [DOI] [PubMed] [Google Scholar]
  25. Ojcius D. M., Young J. D. Cell-mediated killing: effector mechanisms and mediators. Cancer Cells. 1990 May;2(5):138–145. [PubMed] [Google Scholar]
  26. Pasternack M. S., Verret C. R., Liu M. A., Eisen H. N. Serine esterase in cytolytic T lymphocytes. Nature. 1986 Aug 21;322(6081):740–743. doi: 10.1038/322740a0. [DOI] [PubMed] [Google Scholar]
  27. Scott P., Natovitz P., Coffman R. L., Pearce E., Sher A. Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med. 1988 Nov 1;168(5):1675–1684. doi: 10.1084/jem.168.5.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Simon M. M., Hoschützky H., Fruth U., Simon H. G., Kramer M. D. Purification and characterization of a T cell specific serine proteinase (TSP-1) from cloned cytolytic T lymphocytes. EMBO J. 1986 Dec 1;5(12):3267–3274. doi: 10.1002/j.1460-2075.1986.tb04638.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Simon M. M., Kramer M. D., Prester M., Gay S. Mouse T-cell associated serine proteinase 1 degrades collagen type IV: a structural basis for the migration of lymphocytes through vascular basement membranes. Immunology. 1991 May;73(1):117–119. [PMC free article] [PubMed] [Google Scholar]
  30. Simon M. M., Prester M., Nerz G., Kramer M. D., Fruth U. Release of biologically active fragments from human plasma-fibronectin by murine T cell-specific proteinase 1 (TSP-1). Biol Chem Hoppe Seyler. 1988 May;369 (Suppl):107–112. [PubMed] [Google Scholar]
  31. Slade S. J., Langhorne J. Production of interferon-gamma during infection of mice with Plasmodium chabaudi chabaudi. Immunobiology. 1989 Oct;179(4-5):353–365. doi: 10.1016/S0171-2985(89)80041-5. [DOI] [PubMed] [Google Scholar]
  32. Solbach W., Forberg K., Kammerer E., Bogdan C., Röllinghoff M. Suppressive effect of cyclosporin A on the development of Leishmania tropica-induced lesions in genetically susceptible BALB/c mice. J Immunol. 1986 Jul 15;137(2):702–707. [PubMed] [Google Scholar]
  33. Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tada H., Shiho O., Kuroshima K., Koyama M., Tsukamoto K. An improved colorimetric assay for interleukin 2. J Immunol Methods. 1986 Nov 6;93(2):157–165. doi: 10.1016/0022-1759(86)90183-3. [DOI] [PubMed] [Google Scholar]
  35. Takayama H., Trenn G., Humphrey W., Jr, Bluestone J. A., Henkart P. A., Sitkovsky M. V. Antigen receptor-triggered secretion of a trypsin-type esterase from cytotoxic T lymphocytes. J Immunol. 1987 Jan 15;138(2):566–569. [PubMed] [Google Scholar]
  36. Vettel U., Brunner G., Bar-Shavit R., Vlodavsky I., Kramer M. D. Charge-dependent binding of granzyme A (MTSP-1) to basement membranes. Eur J Immunol. 1993 Jan;23(1):279–282. doi: 10.1002/eji.1830230144. [DOI] [PubMed] [Google Scholar]
  37. Watson J. Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J Exp Med. 1979 Dec 1;150(6):1510–1519. doi: 10.1084/jem.150.6.1510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Young J. D., Leong L. G., Liu C. C., Damiano A., Wall D. A., Cohn Z. A. Isolation and characterization of a serine esterase from cytolytic T cell granules. Cell. 1986 Oct 24;47(2):183–194. doi: 10.1016/0092-8674(86)90441-1. [DOI] [PubMed] [Google Scholar]

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