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

• Published in: The Journal of immunology (1950) Vol. 178; no. 11; pp. 7018 - 7031
• Main Authors: Turnquist, Heth R, Raimondi, Giorgio, Zahorchak, Alan F, Fischer, Ryan T, Wang, Zhiliang, Thomson, Angus W
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.06.2007
• Subjects: Animals; Bone Marrow Cells - drug effects; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Down-Regulation - immunology; Epitopes, T-Lymphocyte - immunology; Forkhead Transcription Factors - biosynthesis; Heart Transplantation - immunology; Histocompatibility Antigens Class II - biosynthesis; Histocompatibility Antigens Class II - metabolism; Immunosuppressive Agents - pharmacology; Isoantigens - immunology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Sirolimus - pharmacology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transplantation Tolerance - drug effects; Transplantation Tolerance - immunology; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.178.11.7018

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.