Journal
BLOOD
Volume 125, Issue 19, Pages 2937-2947Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-09-599266
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Funding
- National Institute of Health from the National Heart, Lung and Blood Institute [P01 HL078810]
- National Institute of Health from the National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK052510]
- National Institute of Health from the National Institute of Allergy and Infectious Diseases [R01 AI51390, T32 AI007110]
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CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) are critical elements for maintaining immune tolerance, for instance to exogenous antigens that are introduced during therapeutic interventions such as cell/organ transplant or gene/protein replacement therapy. Co-administration of antigen with rapamycin simultaneously promotes deletion of conventional CD4(+) 1 T cells and induction of Treg. Here, we report that the cytokine FMS-like receptor tyrosine kinase ligand (Flt3L) enhances the in vivo effect of rapamycin. This occurs via selective expansion of plasmacytoid dendritic cells (pDCs), which further augments the number of Treg. Whereas in conventional DCs, rapamycin effectively blocks mammalian target of rapamycin (mTOR) 1 signaling induced by Flt3L, increased mTOR1 activity renders pDCs more resistant to inhibition by rapamycin. Consequently, Flt3L and rapamycin synergistically promote induction of antigen-specific Treg via selective expansion of pDCs. This concept is supported by the finding that Treg induction is abrogated upon pDC depletion. The combination with pDCs and rapamycin is requisite for Flt3L/antigen-induced Treg induction because Flt3L/antigen by itself fails to induce Treg. As coadministering Flt3L, rapamycin, and antigen blocked CD8(+) T-cell and antibody responses in models of gene and protein therapy, we conclude that the differential effect of rapamycin on DC subsets can be exploited for improved tolerance induction.
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