Two synthetic immunodominant and nonencephalitogenic peptides of myelin basic protein, N1-20 and AcN9-20, effectively compete with an encephalitogenic peptide, AcN1-11, in an in vitro T-cell response restricted by class II major histocompatibility complex products
The peptide p89-101 (Val-His-Phe-Phe-LysAsn-lle-Val-Thr-Pro-Arg-Thr-Pro) of myelin basic protein is encephalitogenic in mice expressing H-2q and H-2S antigens. Six of 13 encephalitogen-specific T-cell clones were shown to express the variable a-chain (Va) 17a gene product (KJ23a'), whereas seven clones were KJ23a-. Both KJ23a' and KJ23a-subpopulations were encephalitogenic in'SJL/J mice when adoptively transferred. Depletion of KJ23a+ cells in vivo with the administration of the antibody KJ23a suppresses expenmental allergic encephalomyelitis induced with KJ23a+ T-cell lines. However, experimental allergic encephalomyelitis induced with either (i) encephalitogenic peptide p89-101, (u) intact myelin basic protein, or (iii) KJ23a-T cells reactive to p89-101 cannot be prevented with monoclonal antibody KJ23a.These data indicate that in spite of the V. 17a gene expression in a relatively large proportion of p89-101-specific T cells, such Vp, gene use is not essential for the induction of experimental allergic encephalomyelitis in SJL/J mice. These results contrast with the predominance of V,9 gene use (V, 8.2) in T cells reactive to the encephalitogenic fragment (pR1-11) in PL/J mice. One reason for this lack of dominant use of a particular T-cell receptor V.3 gene family in the autoimmune response to myelin basic protein in SJL/J mice stems from the observation that two encephalitogenic epitopes exist in p89-101. KJ23a-T cells are stimulated by the deleted peptide p89-100, whereas KJ23a+ T cells are not. Thus, in the response to an encephalitogenic fragment of myelin basic protein containing two nested epitopes, at least two distinct T-cell receptor Vl genes are expressed. These distinct T-cell subpopulations can each trigger experimental allergic encepbalomyelitis. These rmdings have implications for therapy of autoimmune disease with antibodies to the T-cell receptor gene products. In this communication we examined another highly susceptible homozygous mouse strain, SJL/J, which lacks the VP3 8 gene family (8) that is predominantly expressed in encephalitogenic T-cell clones from PL/J mice. In SJL/J mice, an encephalitogenic epitope (p89-101) of MBP was characterized (9). Encephalitogenic T-cell clones specific for this determinant are available (10). Furthermore, a monoclonal antibody, KJ23a, against the TCR V.3 17a gene product has been produced by Kappler et al. (11). The initial studies revealed that the SJL/J-derived encephalitogenic T-cell clone 4b.14a (14a) was positively stained with KJ23a antibody. To determine whether preferential use of a single V3 gene exists in SJL/J mice, we examined the contribution of this V.3 gene to the pathogenesis of EAE in this strain. It was found that about half of the independently derived p89-101-specific T-cell clones are KJ23a+. Moreover, the KJ23a-T cells are also encephalitogenic. In addition, we show that there is more than one encephalitogenic epitope within p89-101; KJ23a-T cells recognize a nested epitope within p89-101-namely, p89-100.
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