Abstract
Purified group A streptococcal M proteins were used to stimulate peripheral blood lymphocytes from normal adult volunteers. The activated lymphocytes were cytotoxic against cultured human heart cells, as well as liver cells, fibroblasts, and K562 cells, but showed only minimal cytotoxicity against several animal cell types. The cytotoxic activity evoked by type 5 M protein was dose and time dependent. Rabbit antisera against pep M5 that contained heart- crossreactive antibodies partially inhibited cytotoxicity against heart cells, but had no effect on other target cells, suggesting that a fraction of the effector lymphocytes may be recognizing M protein- crossreactive cell surface antigens. All of the cytotoxic activity was recovered from a CD3+ population of lymphocytes obtained from a fluorescence-activated cell sorter, and CD4+ and CD8+ cells were also cytotoxic. M protein-responsive T cell clones were generated that showed specificity for heart and K562 cells, in addition to clones that were cytotoxic against both cell lines. Our data show that streptococcal M protein evokes cytotoxic T lymphocytes against multiple human but not animal target cells. Some of the effector cells may be specific for cultured myocardial cells, but their role in the pathogenesis of rheumatic carditis will require further studies of lymphocytes from patients with acute rheumatic fever and carditis.
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- Beachey E. H., Seyer J. M., Dale J. B., Simpson W. A., Kang A. H. Type-specific protective immunity evoked by synthetic peptide of Streptococcus pyogenes M protein. Nature. 1981 Jul 30;292(5822):457–459. doi: 10.1038/292457a0. [DOI] [PubMed] [Google Scholar]
- Beachey E. H., Stollerman G. H., Chiang E. Y., Chiang T. M., Seyer J. M., Kang A. H. Purification and properties of M protein extracted from group A streptococci with pepsin: covalent structure of the amino terminal region of type 24 M antigen. J Exp Med. 1977 Jun 1;145(6):1469–1483. doi: 10.1084/jem.145.6.1469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brenner M. B., McLean J., Scheft H., Riberdy J., Ang S. L., Seidman J. G., Devlin P., Krangel M. S. Two forms of the T-cell receptor gamma protein found on peripheral blood cytotoxic T lymphocytes. Nature. 1987 Feb 19;325(6106):689–694. doi: 10.1038/325689a0. [DOI] [PubMed] [Google Scholar]
- Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
- Cunningham M. W., Krisher K., Graves D. C. Murine monoclonal antibodies reactive with human heart and group A streptococcal membrane antigens. Infect Immun. 1984 Oct;46(1):34–41. doi: 10.1128/iai.46.1.34-41.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dale J. B., Beachey E. H. Epitopes of streptococcal M proteins shared with cardiac myosin. J Exp Med. 1985 Aug 1;162(2):583–591. doi: 10.1084/jem.162.2.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dale J. B., Beachey E. H. Multiple, heart-cross-reactive epitopes of streptococcal M proteins. J Exp Med. 1985 Jan 1;161(1):113–122. doi: 10.1084/jem.161.1.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dale J. B., Beachey E. H. Protective antigenic determinant of streptococcal M protein shared with sarcolemmal membrane protein of human heart. J Exp Med. 1982 Oct 1;156(4):1165–1176. doi: 10.1084/jem.156.4.1165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dale J. B., Beachey E. H. Sequence of myosin-crossreactive epitopes of streptococcal M protein. J Exp Med. 1986 Nov 1;164(5):1785–1790. doi: 10.1084/jem.164.5.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dale J. B., Simpson W. A., Ofek I., Beachey E. H. Blastogenic responses of human lymphocytes to structurally defined polypeptide fragments of streptococcal M protein. J Immunol. 1981 Apr;126(4):1499–1505. [PubMed] [Google Scholar]
- Grimm E. A., Ramsey K. M., Mazumder A., Wilson D. J., Djeu J. Y., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. II. Precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus-derived lymphocytes, and natural killer cells. J Exp Med. 1983 Mar 1;157(3):884–897. doi: 10.1084/jem.157.3.884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- KAPLAN M. H. IMMUNOLOGIC RELATION OF STREPTOCOCCAL AND TISSUE ANTIGENS. I. PROPERTIES OF AN ANTIGEN IN CERTAIN STRAINS OF GROUP A STREPTOCOCCI EXHIBITING AN IMMUNOLOGIC CROSS-REACTION WITH HUMAN HEART TISSUE. J Immunol. 1963 Apr;90:595–606. [PubMed] [Google Scholar]
- KAPLAN M. H., MEYESERIAN M. An immunological cross-reaction between group-A streptococcal cells and human heart tissue. Lancet. 1962 Apr 7;1(7232):706–710. doi: 10.1016/s0140-6736(62)91653-7. [DOI] [PubMed] [Google Scholar]
- Kaplan M. H. Cross-reaction of group A streptococci and heart tissue: varying serologic specificity of cross-reactive antisera and relation to carrier-hapten specificity. Transplant Proc. 1969 Dec;1(4):976–980. [PubMed] [Google Scholar]
- Krisher K., Cunningham M. W. Myosin: a link between streptococci and heart. Science. 1985 Jan 25;227(4685):413–415. doi: 10.1126/science.2578225. [DOI] [PubMed] [Google Scholar]
- Lanier L. L., Phillips J. H., Hackett J., Jr, Tutt M., Kumar V. Natural killer cells: definition of a cell type rather than a function. J Immunol. 1986 Nov 1;137(9):2735–2739. [PubMed] [Google Scholar]
- Lanier L. L., Ruitenberg J. J., Phillips J. H. Human CD3+ T lymphocytes that express neither CD4 nor CD8 antigens. J Exp Med. 1986 Jul 1;164(1):339–344. doi: 10.1084/jem.164.1.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lyampert I. M., Vvedenskaya O. I., Danilova T. A. Study on streptococcus group A antigens common with heart tissue elements. Immunology. 1966 Oct;11(4):313–320. [PMC free article] [PubMed] [Google Scholar]
- Ortaldo J. R., Bonnard G. D., Herberman R. B. Cytotoxic reactivity of human lymphocytes cultured in vitro. J Immunol. 1977 Oct;119(4):1351–1357. [PubMed] [Google Scholar]
- Postlethwaite A. E., Snyderman R., Kang A. H. The chemotactic attraction of human fibroblasts to a lymphocyte-derived factor. J Exp Med. 1976 Nov 2;144(5):1188–1203. doi: 10.1084/jem.144.5.1188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saito M., Ichimura O., Kataoka M., Moriya Y., Ueno K., Sugawara Y., Nanjo M., Ishida N. Pronounced antitumor effect of LAK-like cells induced in the peritoneal cavity of mice after intraperitoneal injection of OK-432, a killed streptococcal preparation. Cancer Immunol Immunother. 1986;22(3):161–168. doi: 10.1007/BF00200027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sugamura K., Tanaka Y., Hinuma Y. Two distinct human cloned T cell lines that exhibit natural killer-like and anti-human effector activities. J Immunol. 1982 Apr;128(4):1749–1752. [PubMed] [Google Scholar]
- Tarkkanen J., Saxén H., Nurminen M., Mäkelä P. H., Saksela E. Bacterial induction of human activated lymphocyte killing and its inhibition by lipopolysaccharide (LPS). J Immunol. 1986 Apr 1;136(7):2662–2669. [PubMed] [Google Scholar]
- Uchida A., Micksche M. Lysis of fresh human tumor cells by autologous peripheral blood lymphocytes and pleural effusion lymphocytes activated by OK432. J Natl Cancer Inst. 1983 Oct;71(4):673–680. [PubMed] [Google Scholar]
- Wakasugi H., Oshimi K., Kasahara T., Miyata M., Morioka Y. In vitro augmentation of human natural killer (NK) cell activity by a streptococcal preparation OK-432 and its extracts, protein M and polysaccharides. Int Arch Allergy Appl Immunol. 1982;67(4):322–328. doi: 10.1159/000233041. [DOI] [PubMed] [Google Scholar]
- Yang L. C., Soprey P. R., Wittner M. K., Fox E. N. Streptococcal-induced cell-mediated-immune destruction of cardiac myofibers in vitro. J Exp Med. 1977 Aug 1;146(2):344–360. doi: 10.1084/jem.146.2.344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zabriskie J. B., Freimer E. H. An immunological relationship between the group. A streptococcus and mammalian muscle. J Exp Med. 1966 Oct 1;124(4):661–678. doi: 10.1084/jem.124.4.661. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zabriskie J. B., Hsu K. C., Seegal B. C. Heart-reactive antibody associated with rheumatic fever: characterization and diagnostic significance. Clin Exp Immunol. 1970 Aug;7(2):147–159. [PMC free article] [PubMed] [Google Scholar]
- de la Hera A., Toribio M. L., Marquez C., Martinez C. Interleukin 2 promotes growth and cytolytic activity in human T3+4-8- thymocytes. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6268–6271. doi: 10.1073/pnas.82.18.6268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van de Rijn I., Zabriskie J. B., McCarty M. Group A streptococcal antigens cross-reactive with myocardium. Purification of heart-reactive antibody and isolation and characterization of the streptococcal antigen. J Exp Med. 1977 Aug 1;146(2):579–599. doi: 10.1084/jem.146.2.579. [DOI] [PMC free article] [PubMed] [Google Scholar]