Internalization and endosomal degradation of receptor-bound antigens regulate the efficiency of cross presentation by human dendritic cells.
Dendritic cells (DCs) can capture extracellular antigens and load resultant peptides on to MHC class I molecules, a process termed cross presentation. The mechanisms of cross presentation remain incompletely understood, particularly in primary human DCs. One unknown is the extent to which antigen delivery to distinct endocytic compartments determines cross presentation efficiency, possibly by influencing antigen egress to the cytosol. We addressed the problem directly and quantitatively by comparing the cross presentation of identical antigens conjugated with antibodies against different DC receptors that are targeted to early or late endosomes at distinct efficiencies. In human BDCA1+ and monocyte-derived DCs, CD40 and mannose receptor targeted antibody conjugates to early endosomes, whereas DEC205 targeted antigen primarily to late compartments. Surprisingly, the receptor least efficient at internalization, CD40, was the most efficient at cross presentation. This did not reflect DC activation by CD40, but rather its relatively poor uptake or intra-endosomal degradation compared with mannose receptor or DEC205. Thus, although both early and late endosomes appear to support cross presentation in human DCs, internalization efficiency, especially to late compartments, may be a negative predictor of activity when selecting receptors for vaccine development.
Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Bithi
B
Chatterjee
Anna
A
Smed-Sörensen
Lillian
L
Cohn
Cécile
C
Chalouni
Richard
R
Vandlen
Byoung-Chul
BC
Lee
Jenifer
J
Widger
Tibor
T
Keler
Lélia
L
Delamarre
Ira
I
Mellman
D000595:Amino Acid Sequence; D000936:Antigen-Antibody Complex / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D045142:Cross-Priming; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology*; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D061251:Primary Cell Culture; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism
D000936:Antigen-Antibody Complex; D015703:Antigens, CD; C443299:CLEC4C protein, human; C093569:DEC-205 receptor; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic