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Novel Exosome-Targeted CD4⁺ T Cell Vaccine Counteracting CD4⁺25⁺ Regulatory T Cell-Mediated Immune Suppression and Stimulating Efficient Central Memory CD8⁺ CTL Responses¹

Siguo Hao^*, Yongqing Liu^*, Jinying Yuan^*, Xueshu Zhang^*, Tianpei He^*, Xiaochu Wu, Yangdou Wei, Deming Sun and Jim Xiang^2,*

^* Department of Oncology and Immunology and Department of Biology, Research Unit, Division of Health Research, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; and Kentucky Lions Eye Center, University of Louisville, Louisville, KY 40202

T cell-to-T cell Ag presentation is increasingly attracting attention. In this study, we demonstrated that active CD4⁺ T (aT) cells with uptake of OVA-pulsed dendritic cell-derived exosome (EXO_OVA) express exosomal peptide/MHC class I and costimulatory molecules. These EXO_OVA-uptaken (targeted) CD4⁺ aT cells can stimulate CD8⁺ T cell proliferation and differentiation into central memory CD8⁺ CTLs and induce more efficient in vivo antitumor immunity and long-term CD8⁺ T cell memory responses than OVA-pulsed dendritic cells. They can also counteract CD4⁺25⁺ regulatory T cell-mediated suppression of in vitro CD8⁺ T cell proliferation and in vivo CD8⁺ CTL responses and antitumor immunity. We further elucidate that the EXO_OVA-uptaken (targeted)CD4⁺ aT cell’s stimulatory effect is mediated via its IL-2 secretion and acquired exosomal CD80 costimulation and is specifically delivered to CD8⁺ T cells in vivo via acquired exosomal peptide/MHC class I complexes. Therefore, EXO-targeted active CD4⁺ T cell vaccine may represent a novel and highly effective vaccine strategy for inducing immune responses against not only tumors, but also other infectious diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Research Grants MOP 67230 and 79415 from the Canadian Institutes of Health Research. S.H. was supported by a Postdoctoral Fellowship from Saskatchewan Health Research Foundation.

² Address correspondence and reprint requests to Dr. Jim Xiang, Saskatoon Cancer Center, 20 Campus Drive, Saskatoon, Saskatchewan S7N 4H4, Canada. E-mail address: jxiang{at}scf.sk.ca

³ Abbreviations used in this paper: DC, dendritic cell; EXO, exosome; pMHC, peptide/MHC; DC_OVA, OVA-pulsed DC; EXO_OVA, DC_OVA-derived EXO; aT, active CD4⁺ T; aT_EXO, EXO_OVA-uptaken (targeted) aT; KO, knockout; EXO_CFSE, CFSE-labeled EXO; nT, naive OVA-specific T; Tr, regulatory T; nT_EXO, nT cocultured with EXO_OVA; Tm, memory T; emCTL, effector memory CTL; cmCTL, central memory CTL; ECD, energy-coupled dye.