title: Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell-dependent induction of CD4+CD25+FoxP3+ Treg.
abstract: 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. Coadministration of antigen with rapamycin simultaneously promotes deletion of conventional CD4(+) 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 co-administering 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.
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL; and.
authors.forename: Moanaro
authors.initials: M
authors.lastname: Biswas
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL; and.
authors.forename: Debalina
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL; and.
authors.forename: Sandeep R P
authors.initials: SR
authors.lastname: Kumar
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL; and.
authors.forename: Sushrusha
authors.initials: S
authors.lastname: Nayak
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL; and.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Rogers
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Markusic
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA.
authors.forename: Gongxian
authors.initials: G
authors.lastname: Liao
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA.
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL; and.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004357:Drug Synergism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; C084881:flt3 ligand protein; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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