The effect of the immunosuppressant FK‐506 on alternate pathways of T cell activation

European Journal of Immunology - Tập 21 Số 2 - Trang 439-445 - 1991
Barbara E. Bierer1,2,3,4, Stuart L. Schreiber5, Steven J. Burakoff6,3
1Dana-Farber Cancer Institute, Hematology Division, Boston
2§Department of Medicine, Harvard Medical School, Boston
3Division of Pediatric Oncology, Boston
4Recipient of a McDonnell Scholar Award from the James S. McDonnell Foundation and of a Clinician-Scientist Award from the American Heart Association.
5Department of Medicine, Brigham and Women's Hospital, Department of Chemistry, Harvard University, Boston
6Department of Pediatrics, Harvard Medical School, Boston

Tóm tắt

AbstractStructurally unrelated, FK‐506 and cyclosporin (CsA) bind to and inhibit the action of distinct cytoplasmic receptors, FK‐506‐binding protein (FKBP) and cyclophilin (CyP), respectively. These receptors, termed immunophilins, share no sequence similarity, and yet both have been demonstrated to be capable of catalyzing the cis‐trans isomerization of peptidyl‐prolyl bonds (rotamase activity). Because FK‐506 and CsA bind to different intracellular target structures, we investigated the spectrum of action of FK‐506, in comparison to CsA, on T cell activation. We have shown that FK‐506, like CsA, is able to inhibit T cell activation mediated not only by the T cell receptor‐CD3 complex, but also via another surface molecule, CD2. T cell proliferation, stimulation of interleukin 2 production, and induction of apoptosis were all sensitive to inhibition by both FK‐506 and CsA. With each parameter of activation, FK‐506 is approximately 10‐100‐fold more effective than CsA. In contrast, FK‐506 did not affect T cell proliferation induced by anti‐CD28 monoclonal antibody in the presence of phorbol 12‐myristate 13‐acetate. This CD28 pathway, however, was inhibitable by a structural homolog of FK‐506, rapamycin, demonstrating that the mechanism of action of FK‐506 has specificity. These data suggest that immunophilins or the complex of drug coupled to immunophilin (i.e. FK‐506/FKBP, CsA/CyP) are involved in and regulate selective pathways of T cell stimulation.

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European Journal of Immunology

Tập 21 Số 2

439-445

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