Formation of Immune Complexes with a Tetanus-Derived B Cell Epitope Boosts Human T Cell Responses to Covalently Linked Peptides in an Ex Vivo Blood Loop System

• Published in: The Journal of immunology (1950) Vol. 201; no. 1; pp. 87 - 97
• Main Authors: Fletcher, Erika A K, van Maren, Wendy, Cordfunke, Robert, Dinkelaar, Jasper, Codee, Jeroen D C, van der Marel, Gijs, Melief, Cornelis J M, Ossendorp, Ferry, Drijfhout, Jan Wouter, Mangsbo, Sara M
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.07.2018
• Subjects: Adenomatous polyposis coli; Antigen-antibody complexes; Antigen-presenting cells; Blood; Cancer; CD1c antigen; CD8 antigen; Complement component C1q; Dendritic cells; Epitopes; Human behavior; Immunogenicity; Immunological tolerance; Lymphocytes; Lymphocytes B; Lymphocytes T; Major histocompatibility complex; Monocytes; Peptides; T cell receptors; Tetanus; Tetanus toxin; Vaccines
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1700911

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.