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 Turnquist, H. R. Articles by Thomson, A. W. Search for Related Content PubMed PubMed Citation Articles by Turnquist, H. R. Articles by Thomson, A. W.

Rapamycin-Conditioned Dendritic Cells Are Poor Stimulators of Allogeneic CD4⁺ T Cells, but Enrich for Antigen-Specific Foxp3⁺ T Regulatory Cells and Promote Organ Transplant Tolerance¹

Hth R. Turnquist^2,*,, Giorgio Raimondi^2,*,, Alan F. Zahorchak^*,, Ryan T. Fischer^*,, Zhiliang Wang^*, and Angus W. Thomson^3,*,,

^* Thomas E. Starzl Transplantation Institute, Department of Surgery, and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

The ability of dendritic cells (DC) to regulate Ag-specific immune responses via their influence on T regulatory cells (Treg) may be key to their potential as therapeutic tools or targets for the promotion/restoration of tolerance. In this report, we describe the ability of maturation-resistant, rapamycin (RAPA)-conditioned DC, which are markedly impaired in Foxp3^– T cell allostimulatory capacity, to favor the stimulation of murine alloantigen-specific CD4⁺CD25⁺Foxp3⁺ Treg. This was distinct from control DC, especially following CD40 ligation, which potently expanded non-Treg. RAPA-DC-stimulated Treg were superior alloantigen-specific suppressors of T effector responses compared with those stimulated by control DC. Supporting the ability of RAPA to target effector T and B cells, but permit the proliferation and suppressive function of Treg, an infusion of recipient-derived alloantigen-pulsed RAPA-DC followed by a short postoperative course of low-dose RAPA promoted indefinite (>100 day) heart graft survival. This was associated with graft infiltration by CD4⁺Foxp3⁺ Treg and the absence of transplant vasculopathy. The adoptive transfer of CD4⁺ T cells from animals with long-surviving grafts conferred resistance to rejection. These novel findings demonstrate that, whereas maturation resistance does not impair the capacity of RAPA-DC to modulate Treg, it profoundly impairs their ability to expand T effector cells. A demonstration of this mechanism endorses their potential as tolerance-promoting cellular vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01DK49745, R01AI41011, and R01AI60994 (to A.W.T.). H.R.T. was supported by National Institutes of Health Grant T32CA082084 and a nonconcurrent American Society of Transplantation Basic Science Fellowship, G.R. by a research training fellowship from The Transplantation Society, and R.T.F. by National Institutes of Health Grant T32DK71492.

² H.R.T. and G.R. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Angus W. Thomson, Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Thomas E. Starzl Transplantation Institute, 200 Lothrop Street, Biomedical Science Tower, Room W1540, Pittsburgh, PA 15213. E-mail address: thomsonaw{at}upmc.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; 7-AAD, 7-aminoactinomycin D; BM, bone marrow; B10, C57BL/10; C3H, C3H/HeJ; CTR, control; Cy, cyanine; DAPI, 4',6-diamidino-2-phenylindole, dihydrochloride; Foxp3, Forkhead/winged helix protein-3; M, macrophage; MFI, mean fluorescence intensity; MST, median graft survival time; mTOR, mammalian target of rapamycin; RAPA, rapamycin; RPA, RNase protection assay; Treg, T regulatory cell.

This article has been cited by other articles:

				M. R. Janes and D. A. Fruman Immune Regulation by Rapamycin: Moving Beyond T Cells Sci. Signal., April 21, 2009; 2(67): pe25 - pe25. [Abstract] [Full Text] [PDF]

				A. E. Anderson, D. J. Swan, B. L. Sayers, R. A. Harry, A. M. Patterson, A. von Delwig, J. H. Robinson, J. D. Isaacs, and C. M. U. Hilkens LPS activation is required for migratory activity and antigen presentation by tolerogenic dendritic cells J. Leukoc. Biol., February 1, 2009; 85(2): 243 - 250. [Abstract] [Full Text] [PDF]

				A W Thomson and P D Robbins Tolerogenic dendritic cells for autoimmune disease and transplantation Ann Rheum Dis, December 1, 2008; 67(Suppl_3): iii90 - iii96. [Abstract] [Full Text] [PDF]

				C. Lagaraine, R. Lemoine, C. Baron, H. Nivet, F. Velge-Roussel, and Y. Lebranchu Induction of human CD4+ regulatory T cells by mycophenolic acid-treated dendritic cells J. Leukoc. Biol., October 1, 2008; 84(4): 1057 - 1064. [Abstract] [Full Text] [PDF]

				W. Reichardt, C. Durr, D. von Elverfeldt, E. Juttner, U. V. Gerlach, M. Yamada, B. Smith, R. S. Negrin, and R. Zeiser Impact of Mammalian Target of Rapamycin Inhibition on Lymphoid Homing and Tolerogenic Function of Nanoparticle-Labeled Dendritic Cells following Allogeneic Hematopoietic Cell Transplantation J. Immunol., October 1, 2008; 181(7): 4770 - 4779. [Abstract] [Full Text] [PDF]

				H. R. Turnquist, T. L. Sumpter, A. Tsung, A. F. Zahorchak, A. Nakao, G. J. Nau, F. Y. Liew, D. A. Geller, and A. W. Thomson IL-1{beta}-Driven ST2L Expression Promotes Maturation Resistance in Rapamycin-Conditioned Dendritic Cells J. Immunol., July 1, 2008; 181(1): 62 - 72. [Abstract] [Full Text] [PDF]

				T. Fehr, F. Haspot, J. Mollov, M. Chittenden, T. Hogan, and M. Sykes Alloreactive CD8 T Cell Tolerance Requires Recipient B Cells, Dendritic Cells, and MHC Class II J. Immunol., July 1, 2008; 181(1): 165 - 173. [Abstract] [Full Text] [PDF]