Abstract
Experimental allergic encephalomyelitis (EAE) is an autoimmune disease that can be induced in laboratory animals by immunization with the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP). We analyzed the role of the T cell receptor (TCR) repertoire in susceptibility to EAE induced by these two autoantigens. Autoreactive T cells induced after immunization with MBP use a limited set of TCR. In contrast, we demonstrate that T cell clones that recognize the encephalitogenic PLP epitope (PLP 139-151) use diverse TCR genes. When the TCR repertoire is limited by introduction of a novel rearranged TCR V beta 8.2 chain in transgenic SJL mice, EAE could be induced in the transgenic mice by immunization with the encephalitogenic epitopes of PLP, but not with the encephalitogenic epitope of MBP. Thus, skewing the TCR repertoire affects the susceptibility to EAE by immunization with MBP but not with PLP. These data demonstrate the biological consequences of the usage of a more diverse T cell repertoire in the development of an autoimmune disease.
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Selected References
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- Acha-Orbea H., Mitchell D. J., Timmermann L., Wraith D. C., Tausch G. S., Waldor M. K., Zamvil S. S., McDevitt H. O., Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263–273. doi: 10.1016/0092-8674(88)90558-2. [DOI] [PubMed] [Google Scholar]
- Behlke M. A., Chou H. S., Huppi K., Loh D. Y. Murine T-cell receptor mutants with deletions of beta-chain variable region genes. Proc Natl Acad Sci U S A. 1986 Feb;83(3):767–771. doi: 10.1073/pnas.83.3.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Broeren C. P., Verjans G. M., Van Eden W., Kusters J. G., Lenstra J. A., Logtenberg T. Conserved nucleotide sequences at the 5' end of T cell receptor variable genes facilitate polymerase chain reaction amplification. Eur J Immunol. 1991 Mar;21(3):569–575. doi: 10.1002/eji.1830210306. [DOI] [PubMed] [Google Scholar]
- Burns F. R., Li X. B., Shen N., Offner H., Chou Y. K., Vandenbark A. A., Heber-Katz E. Both rat and mouse T cell receptors specific for the encephalitogenic determinant of myelin basic protein use similar V alpha and V beta chain genes even though the major histocompatibility complex and encephalitogenic determinants being recognized are different. J Exp Med. 1989 Jan 1;169(1):27–39. doi: 10.1084/jem.169.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chothia C., Boswell D. R., Lesk A. M. The outline structure of the T-cell alpha beta receptor. EMBO J. 1988 Dec 1;7(12):3745–3755. doi: 10.1002/j.1460-2075.1988.tb03258.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chou C. H., Shapira R., Fritz R. B. Encephalitogenic activity of the small form of mouse myelin basic protein in the SJL/J mouse. J Immunol. 1983 May;130(5):2183–2186. [PubMed] [Google Scholar]
- Danska J. S., Livingstone A. M., Paragas V., Ishihara T., Fathman C. G. The presumptive CDR3 regions of both T cell receptor alpha and beta chains determine T cell specificity for myoglobin peptides. J Exp Med. 1990 Jul 1;172(1):27–33. doi: 10.1084/jem.172.1.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fenton R. G., Marrack P., Kappler J. W., Kanagawa O., Seidman J. G. Isotypic exclusion of gamma delta T cell receptors in transgenic mice bearing a rearranged beta-chain gene. Science. 1988 Aug 26;241(4869):1089–1092. doi: 10.1126/science.2970670. [DOI] [PubMed] [Google Scholar]
- Greer J. M., Kuchroo V. K., Sobel R. A., Lees M. B. Identification and characterization of a second encephalitogenic determinant of myelin proteolipid protein (residues 178-191) for SJL mice. J Immunol. 1992 Aug 1;149(3):783–788. [PubMed] [Google Scholar]
- Heber-Katz E., Acha-Orbea H. The V-region disease hypothesis: evidence from autoimmune encephalomyelitis. Immunol Today. 1989 May;10(5):164–169. doi: 10.1016/0167-5699(89)90174-6. [DOI] [PubMed] [Google Scholar]
- Koop B. F., Wilson R. K., Wang K., Vernooij B., Zallwer D., Kuo C. L., Seto D., Toda M., Hood L. Organization, structure, and function of 95 kb of DNA spanning the murine T-cell receptor C alpha/C delta region. Genomics. 1992 Aug;13(4):1209–1230. doi: 10.1016/0888-7543(92)90039-u. [DOI] [PubMed] [Google Scholar]
- Kotzin B. L., Karuturi S., Chou Y. K., Lafferty J., Forrester J. M., Better M., Nedwin G. E., Offner H., Vandenbark A. A. Preferential T-cell receptor beta-chain variable gene use in myelin basic protein-reactive T-cell clones from patients with multiple sclerosis. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9161–9165. doi: 10.1073/pnas.88.20.9161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kuchroo V. K., Sobel R. A., Laning J. C., Martin C. A., Greenfield E., Dorf M. E., Lees M. B. Experimental allergic encephalomyelitis mediated by cloned T cells specific for a synthetic peptide of myelin proteolipid protein. Fine specificity and T cell receptor V beta usage. J Immunol. 1992 Jun 15;148(12):3776–3782. [PubMed] [Google Scholar]
- Kuchroo V. K., Steele J. K., O'Hara R. M., Jr, Jayaraman S., Selvaraj P., Greenfield E., Kubo R. T., Dorf M. E. Relationships between antigen-specific helper and inducer suppressor T cell hybridomas. J Immunol. 1990 Jul 15;145(2):438–448. [PubMed] [Google Scholar]
- Norton W. T., Poduslo S. E. Myelination in rat brain: method of myelin isolation. J Neurochem. 1973 Oct;21(4):749–757. doi: 10.1111/j.1471-4159.1973.tb07519.x. [DOI] [PubMed] [Google Scholar]
- Padula S. J., Lingenheld E. G., Stabach P. R., Chou C. H., Kono D. H., Clark R. B. Identification of encephalitogenic V beta-4-bearing T cells in SJL mice. Further evidence for the V region disease hypothesis? J Immunol. 1991 Feb 1;146(3):879–883. [PubMed] [Google Scholar]
- Perkins D. L., Wang Y. S., Fruman D., Seidman J. G., Rimm I. J. Immunodominance is altered in T cell receptor (beta-chain) transgenic mice without the generation of a hole in the repertoire. J Immunol. 1991 May 1;146(9):2960–2964. [PubMed] [Google Scholar]
- Rimm I. J., Ghayur T., Gasser D. L., Rosenkrantz K., Burakoff S. J., Seidman J. G., Ferrara J. L. Alloreactive lymphocytes from T cell receptor (beta-chain) transgenic mice do not mediate a graft-versus-host reaction. J Immunol. 1991 Feb 15;146(4):1130–1133. [PubMed] [Google Scholar]
- Sakai K., Sinha A. A., Mitchell D. J., Zamvil S. S., Rothbard J. B., McDevitt H. O., Steinman L. Involvement of distinct murine T-cell receptors in the autoimmune encephalitogenic response to nested epitopes of myelin basic protein. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8608–8612. doi: 10.1073/pnas.85.22.8608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sobel R. A., Kuchroo V. K. The immunopathology of acute experimental allergic encephalomyelitis induced with myelin proteolipid protein. T cell receptors in inflammatory lesions. J Immunol. 1992 Aug 15;149(4):1444–1451. [PubMed] [Google Scholar]
- Sutherland R. M., Paterson Y., Scherle P. A., Gerhard W., Caton A. J. A new mouse T-cell receptor alpha chain variable region family. Immunogenetics. 1991;34(6):372–375. doi: 10.1007/BF01787487. [DOI] [PubMed] [Google Scholar]
- Uematsu Y., Wege H., Straus A., Ott M., Bannwarth W., Lanchbury J., Panayi G., Steinmetz M. The T-cell-receptor repertoire in the synovial fluid of a patient with rheumatoid arthritis is polyclonal. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8534–8538. doi: 10.1073/pnas.88.19.8534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Urban J. L., Kumar V., Kono D. H., Gomez C., Horvath S. J., Clayton J., Ando D. G., Sercarz E. E., Hood L. Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell. 1988 Aug 12;54(4):577–592. doi: 10.1016/0092-8674(88)90079-7. [DOI] [PubMed] [Google Scholar]
- Wilson R. K., Lai E., Concannon P., Barth R. K., Hood L. E. Structure, organization and polymorphism of murine and human T-cell receptor alpha and beta chain gene families. Immunol Rev. 1988 Jan;101:149–172. doi: 10.1111/j.1600-065x.1988.tb00736.x. [DOI] [PubMed] [Google Scholar]
- Wucherpfennig K. W., Ota K., Endo N., Seidman J. G., Rosenzweig A., Weiner H. L., Hafler D. A. Shared human T cell receptor V beta usage to immunodominant regions of myelin basic protein. Science. 1990 May 25;248(4958):1016–1019. doi: 10.1126/science.1693015. [DOI] [PubMed] [Google Scholar]