HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Allen, A. Articles by Powell, J. D. Search for Related Content PubMed PubMed Citation Articles by Allen, A. Articles by Powell, J. D.

The Novel Cyclophilin Binding Compound, Sanglifehrin A, Disassociates G₁ Cell Cycle Arrest from Tolerance Induction¹

Amy Allen^*, Yan Zheng^*, Lawrence Gardner, Meredith Safford^*, Maureen R. Horton and Jonathan D. Powell^2,*

^* Division of Immunology and Hematopoeisis, Department of Oncology, Division of Hematology, and Division of Pulmonary, Department of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231

T cell anergy has been demonstrated to play a role in maintaining peripheral tolerance to self Ags as well as a means by which tumors can evade immune destruction. Although the precise pathways involved in anergy induction have yet to be elucidated, it has been linked to TCR engagement in the setting of cell cycle arrest. Indeed, rapamycin, which inhibits T cell proliferation in G₁, has the ability to promote tolerance even in the presence of costimulation. To better define the role of the cell cycle in regulating anergy induction, we used the novel cyclophilin-binding ligand, sanglifehrin A (SFA). We demonstrate that SFA can inhibit TCR-induced cytokine and chemokine production without preventing TCR-induced anergy. Our data also indicate that despite its ability to induce G₁ arrest, SFA does not induce anergy in the presence of costimulation. Furthermore, although SFA blocks proliferation to exogenous IL-2, it does not prevent IL-2-induced reversal of anergy. When we examined the phosphorylation of 4EBP-1, a downstream substrate of the mammalian target of rapamycin, we found that rapamycin, but not SFA, inhibited the mammalian target of rapamycin activity. Based on these data, we propose that the decision as to whether TCR engagement will lead to productive activation or tolerance is dictated by a rapamycin -inhibitable pathway, independent of the G₁S phase cell cycle progression.

This article has been cited by other articles:

				Y. Zheng, G. M. Delgoffe, C. F. Meyer, W. Chan, and J. D. Powell Anergic T Cells Are Metabolically Anergic J. Immunol., November 15, 2009; 183(10): 6095 - 6101. [Abstract] [Full Text] [PDF]

				Y. Zheng, S. L. Collins, M. A. Lutz, A. N. Allen, T. P. Kole, P. E. Zarek, and J. D. Powell A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy J. Immunol., February 15, 2007; 178(4): 2163 - 2170. [Abstract] [Full Text] [PDF]

				J. Kallen, R. Sedrani, G. Zenke, and J. Wagner Structure of Human Cyclophilin A in Complex with the Novel Immunosuppressant Sanglifehrin A at 1.6 A Resolution J. Biol. Chem., June 10, 2005; 280(23): 21965 - 21971. [Abstract] [Full Text] [PDF]

				D. W. Smith and C. Nagler-Anderson Preventing Intolerance: The Induction of Nonresponsiveness to Dietary and Microbial Antigens in the Intestinal Mucosa J. Immunol., April 1, 2005; 174(7): 3851 - 3857. [Abstract] [Full Text] [PDF]