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 tolerance

Heth R. Turnquist, Giorgio Raimondi, Alan F. Zahorchak, Ryan T. Fischer, Zhiliang Wang, Angus W. Thomson

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7018-7031
Number of pages14
JournalJournal of Immunology
Volume178
Issue number11
DOIs
StatePublished - Jun 1 2007

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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