Chemokine receptor-mediated delivery directs self-tumor antigen efficiently into the class II processing pathway in vitro and induces protective immunity in vivo.
Nonimmunogenic antigens can be efficiently rendered immunogenic by targeting them to antigen-presenting cells via differentially expressed chemokine receptors. For example, self-tumor or HIV antigens genetically fused with proinflammatory chemoattractants elicit potent immune responses and protective antitumor immunity in mice. Herein we demonstrate that the mechanism by which chemokine fusions elicit responses is efficient uptake, processing, and presentation of antigens via the major histocompatibility complex class II pathway. Experiments with inhibitors of intracellular trafficking suggest that chemoattractant fusion proteins, but not antigen alone, were processed and presented through early/late endosomal and Golgi compartments and stimulated antigen-specific CD4+ T cells both in vitro and in vivo. Chemokine fusion also facilitated the presentation of antigen by dendritic cells to an autologous human tumor-specific CD4+ T-cell line. Taking advantage of chemokine redundancy, viral chemokine fusions were equally potent in inducing protective immunity in vivo, providing a possible strategy to circumvent hypothetical, vaccine-induced antihost chemokine autoimmunity, for example, by use of viral chemoattractants in humans.
Biragyn
Arya
A
Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. biragyna@grc.nia.nih.gov
Ruffini
Pier Adelchi
PA
Coscia
Marta
M
Harvey
Linda K
LK
Neelapu
Sattva S
SS
Baskar
Sivasubramanian
S
Wang
Ji-Ming
JM
Kwak
Larry W
LW
D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000737:chemistry*; D001854:Bone Marrow Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D003713:Dendritic Cells / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D015488:HIV Antigens / Q000737:chemistry; D000949:Histocompatibility Antigens Class II / Q000737:chemistry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019707:Receptors, Chemokine / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013997:Time Factors
D000951:Antigens, Neoplasm; D018925:Chemokines; D002630:Chemotactic Factors; D016207:Cytokines; D015488:HIV Antigens; D000949:Histocompatibility Antigens Class II; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; D004247:DNA