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Published online before print July 11, 2007

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(Journal of Leukocyte Biology. 2007;82:829-838.)
© 2007 by Society for Leukocyte Biology

Nonspecific CD4⁺ T cells with uptake of antigen-specific dendritic cell-released exosomes stimulate antigen-specific CD8⁺ CTL responses and long-term T cell memory

Research Unit, Division of Health Research, Saskatchewan Cancer Agency, Departments of Oncology, Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

¹ Correspondence: Saskatoon Cancer Center, 20 Campus Drive, Saskatoon, SK S7N 4H4, Canada. E-mail: jxiang{at}scf.sk.ca

ABSTRACT

Dendritic cell (DC) and DC-derived exosomes (EXO) have been used extensively for tumor vaccination. However, its therapeutic efficiency is limited to only production of prophylactic immunity against tumors. T cells can uptake DC-released EXO. However, the functional effect of transferred exosomal molecules on T cells is unclear. In this study, we demonstrated that OVA protein-pulsed DC-derived EXO (EXO_OVA) can be taken up by Con A-stimulated, nonspecific CD4⁺ T cells derived from wild-type C57BL/6 mice. The active EXO-uptaken CD4⁺ T cells (aT_EXO), expressing acquired exosomal MHC I/OVA I peptide (pMHC I) complexes and costimulatory CD40 and CD80 molecules, can act as APCs capable of stimulating OVA-specific CD8⁺ T cell proliferation in vitro and in vivo and inducing efficient CD4⁺ Th cell-independent CD8⁺ CTL responses in vivo. The EXO_OVA-uptaken CD4⁺ aT_EXO cell vaccine induces much more efficient CD8⁺ T cell responses and immunity against challenge of OVA-transfected BL6-10 melanoma cells expressing OVA in wild-type C57BL/6 mice than EXO_OVA. The in vivo stimulatory effect of the CD4⁺ aT_EXO cell to CD8⁺ T cell responses is mediated and targeted by its CD40 ligand signaling/acquired exosomal CD80 and pMHC I complexes, respectively. In addition, CD4⁺ aT_EXO vaccine stimulates a long-term, OVA-specific CD8⁺ T cell memory. Therefore, the EXO_OVA-uptaken CD4⁺ T cells may represent a new, effective, EXO-based vaccine strategy in induction of immune responses against tumors and other infectious diseases.

Key Words: aT_EXO • pMHC I • T cell vaccine • antitumor immunity