The role of CD8+CD28 regulatory cells in suppressing myasthenia gravis-associated responses by a dual altered peptide ligand.

Abstract

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 in vitro and in vivo MG-associated T cell responses. In the present study, we investigated the role of CD8(+)CD28(-) 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(+)CD28(-) 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(-/-) knockout mice. Moreover, the dual APL did not inhibit the secretion of IFN-gamma by LN cells from CD8(-/-) mice immunized with Torpedo acetylcholine receptor. However, the mRNA expression of IL-10 and TGF-beta by LN cells from CD8(-/-) 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(-/-) and WT mice. Finally, the dual APL-induced CD4(+)CD25(+)Foxp3(+) cells were up-regulated in CD8(-/-) mice to a similar extent to that observed in the WT mice. Thus, we suggest that CD8(+)CD28(-) regulatory cells play a partial role in the mechanism of action by which the dual APL suppresses experimental autoimmune MG-associated T cell responses.

• Authors: Hava Ben-David, Amir Sharabi, Molly Dayan, Michael Sela, Edna Mozes
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 44 Pg. 17459-64 (Oct 30 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17956982 (Publication Type: Journal Article)

Chemical References

• CD28 Antigens
• CD8 Antigens
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-2 Receptor alpha Subunit
• Ligands
• Peptides
• Receptors, Nicotinic
• Transforming Growth Factor beta
• bcl-X Protein
• Interleukin-10
• Caspase 3
• Caspase 8

Topics

• Animals
• CD28 Antigens (metabolism)
• CD4-Positive T-Lymphocytes (metabolism)
• CD8 Antigens (genetics, metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Cell Proliferation
• Cells, Cultured
• Down-Regulation
• Female
• Forkhead Transcription Factors (metabolism)
• Immunization
• Interleukin-10 (metabolism)
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Ligands
• Mice
• Mice, Knockout
• Myasthenia Gravis (immunology, metabolism)
• Peptides (metabolism)
• Receptors, Nicotinic (immunology)
• Torpedo (immunology)
• Transforming Growth Factor beta (metabolism)
• Up-Regulation
• bcl-X Protein (metabolism)