Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells
Madhav V. Dhodapkar, Ralph M. Steinman, Mark Sapp, Hema Desai, Coraleen Fossella, Joseph Krasovsky, Sean M. Donahoe, P. Rod Dunbar, Vincenzo Cerundolo, Douglas F. Nixon, Nina Bhardwaj
Madhav V. Dhodapkar, Ralph M. Steinman, Mark Sapp, Hema Desai, Coraleen Fossella, Joseph Krasovsky, Sean M. Donahoe, P. Rod Dunbar, Vincenzo Cerundolo, Douglas F. Nixon, Nina Bhardwaj
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Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells

Abstract

Dendritic cells (DCs) are potent antigen-presenting cells that initiate protective T-cell immunity in mice. To study the immunogenicity of DCs in humans, we injected 9 healthy subjects subcutaneously with a control injection of autologous monocyte-derived, mature DCs, followed 4–6 weeks later by DCs pulsed with keyhole limpet hemocyanin (KLH), HLA-A*0201–positive restricted influenza matrix peptide (MP), and tetanus toxoid (TT). Four more subjects received these antigens without DCs. Injection of unpulsed DCs, or antigens alone, failed to immunize. Priming of CD4+ T cells to KLH was observed in all 9 subjects injected with KLH-pulsed DCs, and boosting of TT-specific T-cell immunity was seen in 5 of 6 subjects injected with TT-pulsed DCs. Injection of antigen-pulsed DCs led to a severalfold increase in freshly isolated MP-specific, IFN-γ–secreting CD8+ T cells in all 6 HLA-A*0201–positive subjects, as early as 7 days after injection. When T cells were boosted in culture, there was an increase in MHC tetramer–binding cells and cytotoxic T cells after DC vaccination. These data provide the first controlled evidence of the immunogenicity of DCs in humans, and demonstrate that a single injection of mature DCs rapidly expands T-cell immunity.

Authors

Madhav V. Dhodapkar, Ralph M. Steinman, Mark Sapp, Hema Desai, Coraleen Fossella, Joseph Krasovsky, Sean M. Donahoe, P. Rod Dunbar, Vincenzo Cerundolo, Douglas F. Nixon, Nina Bhardwaj

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(a) Boosting of HLA-A*0201 restricted influenza MP-reactive T cells afte...
(a) Boosting of HLA-A*0201 restricted influenza MP-reactive T cells after MP-pulsed DCs. MP-reactive T cells were quantified using an ELISPOT assay. HLA-A*0201 restricted gag peptide served as control. Results are shown as the number of SFCs per 2 × 105 PBMCs, at baseline and 30 days after the injection of control DCs, MP-pulsed DCs, or MP alone without DCs. SEM for all measurements was <20 %. (b) Kinetics of boosting of MP-reactive T cells in a representative subject (D6). MP-reactive T cells were quantified using an ELISPOT assay. HLA-A*0201 restricted gag peptide served as control. For each assay, graded doses of PBMCs (25 × 103 to 2 × 105 cells per well) were incubated with 10 μM influenza MP. Results are shown as the number of SFCs per 2 × 105 PBMCs per well, at various time points. (c) CD8+ nature of the MP-reactive T cells in the ELISPOT assay. The presence of MP-reactive T cells in unseparated PBMCs was compared with that after CD4 and CD8 depletion by panning. Data are from subject D1.