To improve the delivery and uptake of long peptide vaccines to professional antigen presenting cells (APCs; blood monocytes and CD1c+ dendritic cells) and simultaneously activate the APCs, Fletcher et al. conjugated a trimeric tetanus toxin-derived B cell epitope, [MTTE]3 to the long peptides. In a human blood loop system, naturally present anti-tetanus antibodies formed immune complexes (IC) with the conjugate, significantly enhancing antigen-specific T cell recall responses. APC activation and IC uptake was primarily dependent on the complement factor C1q.
Enhancing T cell responses against both viral and tumor Ags requires efficient costimulation and directed delivery of peptide Ags into APCs. Long peptide vaccines are considered favorable vaccine moieties from a clinical perspective, as they can harbor more than one immunogenic epitope enabling treatment of a broader target population. In addition, longer peptides are not extracellularly loaded on MHC class I; rather, they require intracellular processing and will thereby be presented to T cells mainly by professional APCs, thereby avoiding the risk of tolerance induction. The drawback of peptide vaccines regardless of peptide length is that naked peptides are not actively targeted to and taken up by APCs, and the standard nonconjugated adjuvant-peptide mixtures do not ensure cotargeting of the two to the same APC. We have identified a tetanus toxin-derived B cell epitope that can mediate the formation of immune complexes in the presence of circulating Abs. In this study, we show that these immune complexes improve both Ag uptake by APCs (blood monocytes and CD1c(+) dendritic cells) and consequently improve CD8(+) T cell recall responses in a human ex vivo blood loop system. The uptake of the peptide conjugate by blood monocytes is dependent on Abs and the complement component C1q. We envision that this strategy can be used to facilitate active uptake of Ags into APCs to improve T cell responses against pathogens or cancer.
Author Info: (1) Department of Pharmaceutical Biosciences, Science for Life Laboratory, 751 24 Uppsala University, Uppsala, Sweden. Immuneed AB, 752 37 Uppsala, Sweden. (2) Department of Immuno
Author Info: (1) Department of Pharmaceutical Biosciences, Science for Life Laboratory, 751 24 Uppsala University, Uppsala, Sweden. Immuneed AB, 752 37 Uppsala, Sweden. (2) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; and. (3) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; and. (4) Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2300 RA Leiden, the Netherlands. (5) Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2300 RA Leiden, the Netherlands. (6) Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, 2300 RA Leiden, the Netherlands. (7) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; and. (8) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; and. (9) Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; and. (10) Department of Pharmaceutical Biosciences, Science for Life Laboratory, 751 24 Uppsala University, Uppsala, Sweden; sara.mangsbo@farmbio.uu.se. Immuneed AB, 752 37 Uppsala, Sweden.
