J. Biol. Chem., Vol. 269, Issue 1, 94-99, Jan, 1994
Antigen-specific deletion of cloned T cells using peptide-toxin conjugate complexed with purified class II major histocompatibility complex antigen
BR Clark, SV Deshpande, SD Sharma and B Nag
Anergen, Inc., Redwood City, California 94063.
In a previous report, we showed that cloned T cells incubated with soluble,
cognate major histocompatibility complex (MHC) II-peptide complex
internalized the peptide moiety of the complex. Here, we report
antigen-specific deletion of cloned T cells by treatment with soluble,
cognate MHC II-(peptide-toxin) complexes. Toxin (doxorubicin or
mycophenolic acid) was attached to synthetic AcMBP(1-14)Ala4 peptide, an
analog of the natural acetylated NH2-terminal segment, AcMBP(1-14), of rat
myelin basic protein (MBP). IAk-restricted, AcMBP(1-14)-Specific AJ1.2 and
4R3.9 cloned murine T cells were killed by IAk-(AcMBP(1- 14)Ala4-toxin). No
killing resulted from incubating AJ1.2 and 4R3.9 cells with irrelevant MHC
II-(peptide-toxin) or treating IEk- restricted, pigeon cytochrome
c-specific A.E7 cloned murine T cells with IAk-(AcMBP(1-14)Ala4-toxin). T
cell receptor-mediated T cell uptake of the peptide-toxin moiety of
relevant complex was blocked by anti-T cell receptor-alpha/beta antibody
and by excess toxin-free complex. LD50 determinations revealed that cognate
MHC II-(peptide- toxin) killed T cells much more effectively than did
peptide-toxin conjugate alone. Finally, T cell uptake of peptide-toxin and
intracellular release of toxin occurred after incubation with relevant MHC
II-(peptide-toxin) containing radiolabeled toxin. These findings, which
provide the first evidence that cloned T cells can be deleted with soluble,
cognate MHC II-(peptide-toxin) complexes, may have significant clinical
relevance for antigen-specific therapy of autoimmune or other T
cell-mediated diseases.
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