Targeting Ags to conventional dendritic cells can enhance Ag-specific immune responses. Although most studies have focused on the induction of T cell responses, the mechanisms by which targeting improves Ab responses are poorly understood. In this study we present data on the use of human XCL1 (hXCL1) and hXCL2 fusion vaccines in a murine model. We show that the human chemokines bound type 1 conventional dendritic cells (cDC1), and that immunization with influenza virus hemagglutinin fused to hXCL1 or hXCL2 induced full protection against influenza challenge. Surprisingly, the hXCL1- and hXCL2-fusion vaccines induced better long-term protection associated with stronger induction of neutralizing Abs, and more Ab-secreting cells in bone marrow. In contrast, murine Xcl1 fusion vaccines induced stronger CD8+ T cell responses compared with hXCL1. Further analysis revealed that although murine Xcl1 fusion vaccines induced chemotaxis and were rapidly endocytosed by cDC1, hXCL1 and hXCL2 fusion vaccines did not induce chemotaxis, were less efficiently endocytosed, and consequently, remained on the surface. This difference may explain the enhanced induction of Abs when targeting Ag to cDC1 using hXCL1 and hXCL2, and suggests that immune responses can be manipulated in directing Abs or T cells based on how efficiently the targeted Ag is endocytosed by the DC.
This work was supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project 179573/V40 (to L.R., E.S.B., and B.B.), Global Health and Vaccination Research Project 220642 (to E.F.) and Fri prosjektstøtte 250884 (to E.F.), as well as by the Regional Health Authorities (Helse Sør-Øst) (to A.L.) and the K.G. Jebsen Center for Influenza Vaccine Research (to A.G. and B.B.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- Ab-secreting cell
- bone marrow
- type 1 conventional dendritic cell
- dendritic cell
- human embryonic kidney
- hemagglutination inhibition
- human XCL1
- Madin–Darby canine kidney
- MHC class II
- murine Xcl1
- room temperature.
- Received November 3, 2016.
- Accepted January 27, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.