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Immunosuppression by Cyclosporine Cyclophilin A-Deficient Mice Are Cyclophilin A-Deficient Mice Are Resistant to Immunosuppression by Cyclosporine John Colgan, Mohammed Asmal, Bin Yu and Jeremy Luban This information is current as J Immunol 2005; 174:6030-6038; ; of October 2, 2021. doi: 10.4049/jimmunol.174.10.6030 http://www.jimmunol.org/content/174/10/6030 References This article cites 53 articles, 28 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/174/10/6030.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 2, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Cyclophilin A-Deficient Mice Are Resistant to Immunosuppression by Cyclosporine1 John Colgan,2* Mohammed Asmal,* Bin Yu,* and Jeremy Luban3*† Cyclosporine is an immunosuppressive drug that is widely used to prevent organ transplant rejection. Known intracellular ligands for cyclosporine include the cyclophilins, a large family of phylogenetically conserved proteins that potentially regulate protein folding in cells. Immunosuppression by cyclosporine is thought to result from the formation of a drug-cyclophilin complex that binds to and inhibits calcineurin, a serine/threonine phosphatase that is activated by TCR engagement. Amino acids within the cyclophilins that are critical for binding to cyclosporine have been identified. Most of these residues are highly conserved within the 15 mammalian cyclophilins, suggesting that many are potential targets for the drug. We examined the effects of cyclosporine on immune cells and mice lacking Ppia, the gene encoding the prototypical cyclophilin protein cyclophilin A. TCR-induced proliferation and signal transduction by Ppia؊/؊ CD4؉ T cells were resistant to cyclosporine, an effect that was attributable to diminished calcineurin inhibition. Immunosuppressive doses of cyclosporine failed to block the responses of Ppia؊/؊ mice to Downloaded from allogeneic challenge. Rag2؊/؊ mice reconstituted with Ppia؊/؊ splenocytes were also cyclosporine resistant, indicating that this -property is intrinsic to Ppia؊/؊ immune cells. Thus, among multiple potential ligands, CypA is the primary mediator of immu nosuppression by cyclosporine. The Journal of Immunology, 2005, 174: 6030–6038. yclosporine is a cyclic decapeptide produced by the soil ing to conformational stability, or sterically blocking interactions fungi Tolypocladium inflatum. Originally identified in a between factors (7–10). http://www.jimmunol.org/ C screen for novel antibiotics, cyclosporine was shown by Cyclophilin A (CypA), the prototypical member of the cyclo- Borel et al. (1, 2) to be a potent and specific inhibitor of T cell philin family, is a highly conserved protein that is maintained at responses to alloantigens. This discovery led to widespread clinical high levels in mammalian cells (11). Studies of budding yeast have use of cyclosporine as an immunosuppressant, revolutionizing or- shown that CypA localizes to both the cytoplasm and nucleus (12, gan transplantation in humans. 13). Consisting solely of the conserved PPIase domain, CypA Efforts to identify the cellular receptor for cyclosporine (3) led forms a globular, eight-stranded ␤-barrel with a solvent-exposed to discovery of the cyclophilins, one of three protein families hydrophobic pocket that is the binding site for proline-containing known collectively as peptidyl-prolyl isomerases (PPIases)4 (4). peptides as well as the enzymatic active site (14). Cyclosporine by guest on October 2, 2021 Other PPIase families are the FK506-binding proteins (FKBPs) binds with subnanomolar affinity to CypA via contacts within the and the parvulins (4). PPIases catalyze the cis-trans interconver- hydrophobic pocket (15) and inhibits PPIase activity. However, sion of peptide bonds N-terminal to proline, an activity that has this effect is thought to be irrelevant for the immunosuppression. been extensively characterized in vitro using model peptides or Rather, the complex between cyclosporine and CypA creates a denatured proteins as substrates (5). Consistent with a global role composite surface that binds to and inhibits calcineurin (16, 17), a in the folding of nascent proteins in vivo, the distribution of PPI- serine-threonine phosphatase that is activated by calcium. Sub- ases overlaps with the heat shock protein 70 protein family, being strates for calcineurin include members of the NF-AT family of found in all eubacteria, a few archaebacteria, and all eukaryotes, transcription factors (18). Found in the cytoplasm of resting T (6). PPIases also may regulate the function of mature proteins by cells, the NF-ATs are dephosphorylated upon TCR ligation and catalyzing isomerization between alternative structures, contribut- relocate to the nucleus in a functionally active form. In the pres- ence of cyclosporine, dephosphorylation of the NF-ATs is blocked, and expression of genes encoding cytokines and other proteins required for an immune response is inhibited. Departments of *Microbiology and †Medicine, Columbia University College of Phy- sicians and Surgeons, New York, NY 10032 Structural and genetic studies have identified amino acids within Received for publication December 15, 2004. Accepted for publication March CypA that are critical for the formation of a complex with cyclo- 4, 2005. sporine that binds to calcineurin (15, 19–24). In addition to CypA, The costs of publication of this article were defrayed in part by the payment of page the mouse and human genomes each encode 14 other cyclophilins charges. This article must therefore be hereby marked advertisement in accordance (25), most of which are distinguishable from CypA by the presence with 18 U.S.C. Section 1734 solely to indicate this fact. of terminal extensions bearing motifs for subcellular localization 1 This work was supported by grants from the Sandler Foundation for Asthma Re- or binding to nucleic acids or other proteins. Despite these differ- search, National Institutes of Health Grant RO1 AI 36199, and a Pilot and Feasibility Grant from the Columbia University Diabetes and Endocrinology Research Center. ences, the residues in CypA that mediate cyclosporine binding are 2 Current address: Roy J. and Lucille A. Carver College of Medicine, Department of highly conserved in other family members (Table I), indicating Internal Medicine, University of Iowa, 375 Newton Road, Iowa City, IA 52246. that multiple cyclophilins are potential targets for the drug. 3 Address correspondence and reprint requests to Dr. Jeremy Luban, Department of The genome of the budding yeast Saccharomyces cerevisiae en- Microbiology, Columbia University, 701 West 168th Street, New York, NY 10032. codes eight different cyclophilins (26), none of which are essential E-mail address: [email protected] (27). Several studies have demonstrated that CypA is the primary 4 Abbreviations used in this paper: PPIase, peptidyl-prolyl isomerase; BMDDC, bone marrow-derived dendritic cell; CypA/B, cyclophilin A/B; FKBP, FK506-binding mediator of calcineurin inhibition by cyclosporine in this organism protein. (28, 29). Hence, it might be predicted that mammalian CypA Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 6031 Table I. Amino acid alignment of mouse cyclophilinsa Amino Acid Position in PPIA (CypA) Cyclophilin 54 55 60 61 63 72 101 102 103 111 113 121 122 126 PPIA (CypA) His Arg Phe Met Gln Gly Ala Asn Ala Gln Phe Trp Leu His PPIB (CypB) ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– PPIC (CypC) ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– PPID (CypD) ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– His ––– ––– PPIE (CypE) ––– ––– ––– ––– ––– ––– ––– ––– Ser ––– ––– ––– ––– ––– PPIF (CypF) ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– PPIG (CypG) ––– ––– ––– ––– ––– ––– ––– ––– Arg ––– ––– His ––– ––– PPIL1 ––– ––– ––– Val ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– PPIL2 ––– ––– ––– ––– ––– ––– ––– ––– Ser ––– ––– Tyr ––– ––– PPIL3 ––– ––– ––– ––– ––– ––– ––– ––– Asn ––– ––– His ––– Tyr PPIL4 ––– Asn ––– Ile ––– ––– Val ––– Asn ––– Leu Tyr ––– ––– NKTR ––– ––– ––– ––– ––– ––– ––– ––– Arg ––– ––– His ––– ––– RANBP2 ––– ––– Ser Ala ––– ––– Gln ––– ––– Pro Val Gly ––– Gln J08 Riken ––– ––– ––– ––– ––– ––– ––– ––– Ser ––– ––– ––– ––– ––– F20 Riken Asp Pro Leu Gln Phe Lys Ile Asp Val Ala Thr Leu Lys ––– a The residues listed mediate contacts between CypA and cyclosporine based on X–ray crystallographic and nuclear magnetic resonance analysis (see Refs. 15 and 20). Dashes (–––) denote identity to the amino acid at the indicated position in CypA. Downloaded from would mediate the immunosuppressive effects of cyclosporine in T Type Culture Collection and were maintained, as recommended by the cells. In contrast, CypA
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