{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T07:13:38Z","timestamp":1789629218930,"version":"build-2803163510"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"44","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,10,30]]},"abstract":"\n Myasthenia gravis (MG) and experimental autoimmune MG are T cell-dependent antibody-mediated autoimmune diseases. A dual altered peptide ligand (APL), composed of the tandemly arranged two single amino acid analogs of two myasthenogenic peptides, p195-212 and p259-271, down-regulated\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n MG-associated T cell responses. In the present study, we investigated the role of CD8\n +<\/jats:sup>\n CD28\n \u2212<\/jats:sup>\n regulatory cells in the mechanism of action of the dual APL. We demonstrated that treatment of mice with the dual APL concomitant with immunization with a myasthenogenic peptide resulted in an increased population of CD8\n +<\/jats:sup>\n CD28\n \u2212<\/jats:sup>\n cells that express forkhead box P3 (Foxp3). The dual APL inhibited the proliferation of lymph node (LN) cells of the Torpedo acetylcholine receptor-immunized WT C57BL\/6 mice, whereas the inhibition was abrogated in CD8\n \u2212\/\u2212<\/jats:sup>\n knockout mice. Moreover, the dual APL did not inhibit the secretion of IFN-\u03b3 by LN cells from CD8\n \u2212\/\u2212<\/jats:sup>\n mice immunized with Torpedo acetylcholine receptor. However, the mRNA expression of IL-10 and TGF-\u03b2 by LN cells from CD8\n \u2212\/\u2212<\/jats:sup>\n mice was up-regulated similarly to that of the WT mice. Furthermore, the dual APL elevated the proapoptotic markers caspases 3 and caspase 8, whereas it down-regulated the antiapoptotic marker Bcl-xL in both CD8\n \u2212\/\u2212<\/jats:sup>\n and WT mice. Finally, the dual APL-induced CD4\n +<\/jats:sup>\n CD25\n +<\/jats:sup>\n Foxp3\n +<\/jats:sup>\n cells were up-regulated in CD8\n \u2212\/\u2212<\/jats:sup>\n mice to a similar extent to that observed in the WT mice. Thus, we suggest that CD8\n +<\/jats:sup>\n CD28\n \u2212<\/jats:sup>\n regulatory cells play a partial role in the mechanism of action by which the dual APL suppresses experimental autoimmune MG-associated T cell responses.\n <\/jats:p>","DOI":"10.1073\/pnas.0708577104","type":"journal-article","created":{"date-parts":[[2007,10,23]],"date-time":"2007-10-23T21:10:18Z","timestamp":1193173818000},"page":"17459-17464","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":44,"title":["The role of CD8\n +<\/sup>\n CD28\n \u2212<\/sup>\n regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand"],"prefix":"10.1073","volume":"104","author":[{"given":"Hava","family":"Ben-David","sequence":"first","affiliation":[{"name":"Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, 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