Induction of TLR4-dependent CD8+ T cell immunity by murine β-defensin2 fusion protein vaccines

• Published in: Vaccine Vol. 29; no. 18; pp. 3476 - 3482
• Main Authors: Park, H.J, Qin, H, Cha, S.C, Sharma, R, Chung, Y, Schluns, K.S, Neelapu, S.S, Overwijk, W.W, Hwu, P, Kwak, L.W
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 18.04.2011; Elsevier
• Subjects: Adoptive Transfer; Allergy and Immunology; Animals; Antigen-Presenting Cells; antigens; Applied microbiology; beta chemokines; beta-Defensins - immunology; Biological and medical sciences; Cancer vaccine; Cancer Vaccines - immunology; CD8-positive T-lymphocytes; CD8-Positive T-Lymphocytes - immunology; Cross-Priming; Defensin beta 2 (mBD2); dendritic cells; Fundamental and applied biological sciences. Psychology; gp100 Melanoma Antigen - immunology; immunity; immunization; Interferon-gamma - immunology; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Microbiology; ovalbumin; Ovalbumin - immunology; Receptors, CCR6 - immunology; Recombinant Fusion Proteins - immunology; recombinant vaccines; TLR4; Toll-like receptor 4; Toll-Like Receptor 4 - immunology; Tumors; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); TLR4; Cancer vaccine; Defensin beta 2 (mBD2); Peptides; Rodentia; Vaccine; Malignant tumor; Antimicrobial agent; Vertebrata; Mammalia; Mouse; Defensin; Fusion protein; Cancer; CD8 T lymphocyte
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2011.02.061

Abstract Our laboratory previously described the strategy of fusing chemokine receptor ligands to antigens in order to generate immunogenic DNA vaccines. In the present study, we produced mouse β-2 defensin (mBD2) fusion proteins using both ovalbumin (OVA) and gp100 as model antigens. Superior cross-presentation by dendritic cells (DC) was observed for mBD2 fused antigens over unfused antigens in vitro. In vivo , we observed significant increases in the expansion of adoptively transferred antigen-specific MHC class I, but not class II-restricted T cells after immunization with mBD2 fused antigen over antigen alone. This enhanced expansion of class I restricted T cells was Toll-like receptor 4 (TLR4) dependent, but CC chemokine receptor 6 (CCR6) independent. Superior tumor resistance was observed for mBD2-fusion protein vaccines, compared to unfused antigen, in both B16-OVA and B16 tumor models. These data suggest that production of mBD2 fusion proteins is feasible and that the vaccines facilitate in vivo expansion of adoptively transferred T cells through a TLR4-dependent mechanism.