Abstract
Identification of the targets of autoreactive T cells is important for understanding the pathogenesis of many autoimmune diseases. In multiple sclerosis, myelin proteins are thought to be the targets of autoreactive T-cell responses. To date only major histocompatibility complex class II-restricted CD4+ T-cell responses to myelin proteins have been investigated. In the present study, the ability of self peptides derived from human myelin proteins to induce autoreactive CD8+ T-cell responses has been assessed. Peptide sequences from human myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein have been identified that bind to and form stable complexes with HLA-A2. MBP 110-118, PLP 80-88, MAG 287-295, MAG 509-517, and MAG 556-564 were all able to induce peptide-specific HLA-A2-restricted CD8+ cytotoxic T-lymphocyte (CTL) responses in vitro in HLA-A2+ individuals. CTLs specific for MBP 110-118 and MAG 556-564 could recognize endogenously processed antigens presented by HLA-A2. CTL clones reactive to MBP 110-118 and MAG 556-564 produced tumor necrosis factor alpha and a subset of these clones also produced interferon gamma. These results demonstrate that (i) self peptides derived from human myelin proteins can induce autoreactive CD8+ CTLs and (ii) these CD8+ T cells produce cytokines thought to be important in mediating demyelinating disease. These studies provide an experimental approach for the assessment of CD8+ T-cell responses in such autoimmune diseases.
Full text
PDF![10859](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fb4/45125/af32f1b944e1/pnas01145-0110.png)
![10860](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fb4/45125/567f726f517b/pnas01145-0111.png)
![10861](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fb4/45125/46de39d70cc1/pnas01145-0112.png)
![10862](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fb4/45125/ea5ec424281d/pnas01145-0113.png)
![10863](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fb4/45125/4468c065af5a/pnas01145-0114.png)
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
- Booss J., Esiri M. M., Tourtellotte W. W., Mason D. Y. Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis. J Neurol Sci. 1983 Dec;62(1-3):219–232. doi: 10.1016/0022-510x(83)90201-0. [DOI] [PubMed] [Google Scholar]
- Burns J., Rosenzweig A., Zweiman B., Lisak R. P. Isolation of myelin basic protein-reactive T-cell lines from normal human blood. Cell Immunol. 1983 Oct 15;81(2):435–440. doi: 10.1016/0008-8749(83)90250-2. [DOI] [PubMed] [Google Scholar]
- Chou Y. K., Bourdette D. N., Offner H., Whitham R., Wang R. Y., Hashim G. A., Vandenbark A. A. Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. J Neuroimmunol. 1992 May;38(1-2):105–113. doi: 10.1016/0165-5728(92)90095-3. [DOI] [PubMed] [Google Scholar]
- Diehl H. J., Schaich M., Budzinski R. M., Stoffel W. Individual exons encode the integral membrane domains of human myelin proteolipid protein. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9807–9811. doi: 10.1073/pnas.83.24.9807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gotch F., Rothbard J., Howland K., Townsend A., McMichael A. Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2. 1987 Apr 30-May 6Nature. 326(6116):881–882. doi: 10.1038/326881a0. [DOI] [PubMed] [Google Scholar]
- Grenier Y., Ruijs T. C., Robitaille Y., Olivier A., Antel J. P. Immunohistochemical studies of adult human glial cells. J Neuroimmunol. 1989 Feb;21(2-3):103–115. doi: 10.1016/0165-5728(89)90166-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hafler D. A., Benjamin D. S., Burks J., Weiner H. L. Myelin basic protein and proteolipid protein reactivity of brain- and cerebrospinal fluid-derived T cell clones in multiple sclerosis and postinfectious encephalomyelitis. J Immunol. 1987 Jul 1;139(1):68–72. [PubMed] [Google Scholar]
- Hofman F. M., Hinton D. R., Johnson K., Merrill J. E. Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med. 1989 Aug 1;170(2):607–612. doi: 10.1084/jem.170.2.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hogan K. T., Shimojo N., Walk S. F., Engelhard V. H., Maloy W. L., Coligan J. E., Biddison W. E. Mutations in the alpha 2 helix of HLA-A2 affect presentation but do not inhibit binding of influenza virus matrix peptide. J Exp Med. 1988 Aug 1;168(2):725–736. doi: 10.1084/jem.168.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jiang H., Zhang S. I., Pernis B. Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science. 1992 May 22;256(5060):1213–1215. doi: 10.1126/science.256.5060.1213. [DOI] [PubMed] [Google Scholar]
- Johnson D., Hafler D. A., Fallis R. J., Lees M. B., Brady R. O., Quarles R. H., Weiner H. L. Cell-mediated immunity to myelin-associated glycoprotein, proteolipid protein, and myelin basic protein in multiple sclerosis. J Neuroimmunol. 1986 Nov;13(1):99–108. doi: 10.1016/0165-5728(86)90053-6. [DOI] [PubMed] [Google Scholar]
- Kamholz J., de Ferra F., Puckett C., Lazzarini R. Identification of three forms of human myelin basic protein by cDNA cloning. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4962–4966. doi: 10.1073/pnas.83.13.4962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kerlero de Rosbo N., Milo R., Lees M. B., Burger D., Bernard C. C., Ben-Nun A. Reactivity to myelin antigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. J Clin Invest. 1993 Dec;92(6):2602–2608. doi: 10.1172/JCI116875. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koh D. R., Fung-Leung W. P., Ho A., Gray D., Acha-Orbea H., Mak T. W. Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice. Science. 1992 May 22;256(5060):1210–1213. doi: 10.1126/science.256.5060.1210. [DOI] [PubMed] [Google Scholar]
- Liblau R. S., Fugger L. Tumor necrosis factor-alpha and disease progression in multiple sclerosis. N Engl J Med. 1992 Jan 23;326(4):272–273. doi: 10.1056/NEJM199201233260415. [DOI] [PubMed] [Google Scholar]
- Martin R., Jaraquemada D., Flerlage M., Richert J., Whitaker J., Long E. O., McFarlin D. E., McFarland H. F. Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals. J Immunol. 1990 Jul 15;145(2):540–548. [PubMed] [Google Scholar]
- Martin R., McFarland H. F., McFarlin D. E. Immunological aspects of demyelinating diseases. Annu Rev Immunol. 1992;10:153–187. doi: 10.1146/annurev.iy.10.040192.001101. [DOI] [PubMed] [Google Scholar]
- Ota K., Matsui M., Milford E. L., Mackin G. A., Weiner H. L., Hafler D. A. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature. 1990 Jul 12;346(6280):183–187. doi: 10.1038/346183a0. [DOI] [PubMed] [Google Scholar]
- Panitch H. S., Hirsch R. L., Schindler J., Johnson K. P. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology. 1987 Jul;37(7):1097–1102. doi: 10.1212/wnl.37.7.1097. [DOI] [PubMed] [Google Scholar]
- Parker K. C., Bednarek M. A., Coligan J. E. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol. 1994 Jan 1;152(1):163–175. [PubMed] [Google Scholar]
- Pelfrey C. M., Trotter J. L., Tranquill L. R., McFarland H. F. Identification of a novel T cell epitope of human proteolipid protein (residues 40-60) recognized by proliferative and cytolytic CD4+ T cells from multiple sclerosis patients. J Neuroimmunol. 1993 Jul;46(1-2):33–42. doi: 10.1016/0165-5728(93)90231-m. [DOI] [PubMed] [Google Scholar]
- Pette M., Fujita K., Kitze B., Whitaker J. N., Albert E., Kappos L., Wekerle H. Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology. 1990 Nov;40(11):1770–1776. doi: 10.1212/wnl.40.11.1770. [DOI] [PubMed] [Google Scholar]
- Raine C. S. Biology of disease. Analysis of autoimmune demyelination: its impact upon multiple sclerosis. Lab Invest. 1984 Jun;50(6):608–635. [PubMed] [Google Scholar]
- Sato S., Fujita N., Kurihara T., Kuwano R., Sakimura K., Takahashi Y., Miyatake T. cDNA cloning and amino acid sequence for human myelin-associated glycoprotein. Biochem Biophys Res Commun. 1989 Sep 29;163(3):1473–1480. doi: 10.1016/0006-291x(89)91145-5. [DOI] [PubMed] [Google Scholar]
- Selmaj K., Raine C. S., Cross A. H. Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann Neurol. 1991 Nov;30(5):694–700. doi: 10.1002/ana.410300510. [DOI] [PubMed] [Google Scholar]
- Selmaj K., Raine C. S., Farooq M., Norton W. T., Brosnan C. F. Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J Immunol. 1991 Sep 1;147(5):1522–1529. [PubMed] [Google Scholar]
- Sethna M. P., Lampson L. A. Immune modulation within the brain: recruitment of inflammatory cells and increased major histocompatibility antigen expression following intracerebral injection of interferon-gamma. J Neuroimmunol. 1991 Nov;34(2-3):121–132. doi: 10.1016/0165-5728(91)90121-m. [DOI] [PubMed] [Google Scholar]
- Sharief M. K., Thompson E. J. In vivo relationship of tumor necrosis factor-alpha to blood-brain barrier damage in patients with active multiple sclerosis. J Neuroimmunol. 1992 May;38(1-2):27–33. doi: 10.1016/0165-5728(92)90087-2. [DOI] [PubMed] [Google Scholar]
- Storkus W. J., Howell D. N., Salter R. D., Dawson J. R., Cresswell P. NK susceptibility varies inversely with target cell class I HLA antigen expression. J Immunol. 1987 Mar 15;138(6):1657–1659. [PubMed] [Google Scholar]
- Sun J., Link H., Olsson T., Xiao B. G., Andersson G., Ekre H. P., Linington C., Diener P. T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis. J Immunol. 1991 Mar 1;146(5):1490–1495. [PubMed] [Google Scholar]
- Townsend A., Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 1989;7:601–624. doi: 10.1146/annurev.iy.07.040189.003125. [DOI] [PubMed] [Google Scholar]
- Traugott U., Reinherz E. L., Raine C. S. Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science. 1983 Jan 21;219(4582):308–310. doi: 10.1126/science.6217550. [DOI] [PubMed] [Google Scholar]
- Trotter J. L., Hickey W. F., van der Veen R. C., Sulze L. Peripheral blood mononuclear cells from multiple sclerosis patients recognize myelin proteolipid protein and selected peptides. J Neuroimmunol. 1991 Jul;33(1):55–62. doi: 10.1016/0165-5728(91)90034-5. [DOI] [PubMed] [Google Scholar]
- Viskochil D., Cawthon R., O'Connell P., Xu G. F., Stevens J., Culver M., Carey J., White R. The gene encoding the oligodendrocyte-myelin glycoprotein is embedded within the neurofibromatosis type 1 gene. Mol Cell Biol. 1991 Feb;11(2):906–912. doi: 10.1128/mcb.11.2.906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yewdell J. W., Bennink J. R. Cell biology of antigen processing and presentation to major histocompatibility complex class I molecule-restricted T lymphocytes. Adv Immunol. 1992;52:1–123. doi: 10.1016/s0065-2776(08)60875-5. [DOI] [PubMed] [Google Scholar]
- Zhang Y., Burger D., Saruhan G., Jeannet M., Steck A. J. The T-lymphocyte response against myelin-associated glycoprotein and myelin basic protein in patients with multiple sclerosis. Neurology. 1993 Feb;43(2):403–407. doi: 10.1212/wnl.43.2.403. [DOI] [PubMed] [Google Scholar]