Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ …

HR Turnquist, G Raimondi, AF Zahorchak… - The Journal of …, 2007 - journals.aai.org
HR Turnquist, G Raimondi, AF Zahorchak, RT Fischer, Z Wang, AW Thomson
The Journal of Immunology, 2007journals.aai.org
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 …
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.
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