| Autor: |
Horrevorts SK; Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands., Duinkerken S; Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands., Bloem K; Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands.; Centre for Specialized Nutrition, Danone Research, Wageningen, Netherlands., Secades P; Division of Cell Biology, Dutch Cancer Institute, Amsterdam, Netherlands., Kalay H; Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands., Musters RJ; Department of Physiology, VU University Medical Center, Amsterdam, Netherlands., van Vliet SJ; Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands., García-Vallejo JJ; Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands., van Kooyk Y; Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, Netherlands. |
| Abstrakt: |
DC-SIGN is an antigen uptake receptor expressed on dendritic cells (DCs) with specificity for glycans present on a broad variety of pathogens and is capable of directing its cargo to MHC-I and MHC-II pathways for the induction of CD8 + and CD4 + T cell responses, respectively. Therefore, DC-SIGN is a very promising target for the delivery of antigen for anti-cancer vaccination. Although the endocytic route leading to MHC-II presentation is characterized to a large extent, the mechanisms controlling DC-SIGN targeted cross-presentation of exogenous peptides on MHC-I, are not completely resolved yet. In this paper, we used imaging flow cytometry and antigen-specific CD8 + T cells to investigate the intracellular fate of DC-SIGN and its cargo in human DCs. Our data demonstrates that immature DCs and toll-like receptor 4 (TLR4) stimulated DCs had similar internalization capacity and were both able to cross-present antigen targeted via DC-SIGN. Interestingly, simultaneous triggering of TLR4 and DC-SIGN on DCs resulted in the translocation of cargo to the cytosol, leading to proteasome-dependent processing and increased CD8 + T cell activation. Understanding the dynamics of DC-SIGN-mediated uptake and processing is essential for the design of optimal DC-SIGN-targeting vaccination strategies aimed at enhancing CD8 + T cell responses. |
