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CD4+ T cell-released exosomes inhibit CD8+ cytotoxic T-lymphocyte responses and antitumor immunity

Cellular & Molecular Immunology volume 8, pages 23–30 (2011)Cite this article

Abstract

T cells secrete bioactive exosomes (EXO), but the potential immunoregulatory effect of T-cell EXO is largely unknown. In this study, we generated activated ovalbumin (OVA)-specific CD4+ T cells in vitro via coculture of OVA-pulsed dendritic cells (DCOVA) with naive CD4+ T cells derived from OVA-specific T-cell receptor (TCR) transgenic OTII mice. CD4+ T-cell EXO were then purified from the CD4+ T-cell culture supernatants by differential ultracentrifugation. CD4+ T-cell EXO exhibited the ‘saucer’ shape that is characteristic of EXO with a diameter between 50 and 100 nm, as assessed by electron microscopy, and contained the EXO-associated proteins LAMP-1, TCR and lymphocyte function associated antigen-1 (LFA-1), as determined by western blot. Flow cytometric analysis showed that CD4+ T-cell EXO expressed CD4+ T-cell markers (CD4, TCR, LFA-1, CD25 and Fas ligand), but to a lesser extent than CD4+ T cells. We demonstrated that DCOVA took up CD4+ T-cell EXO via peptide/major histocompatibility complex (pMHC) II/TCR and CD54/LFA-1 interactions. OVA-specific CD4+ T-cell EXO from OTII mice, but not ConA-stimulated polyclonal CD4+ T-cell EXO from wild-type C57BL/6 mice inhibited DCOVA-stimulated in vitro CD4+ T-cell proliferation and in vivo CD8+ cytotoxic T lymphocyte (CTL) responses and antitumor immunity against OVA-expressing B16 melanoma BL6-10OVA cells. In addition, EXO derived from a T-cell hybridoma cell line, MF72.2D9, expressing an OVA-specific CD4+ TCR, had a similar inhibitory effect as OTII CD4+ T-cell EXO on CTL-mediated antitumor immunity. Taken together, our data indicate that antigen-specific T-cell EXO may serve as a new type of immunosuppressive reagent for use in transplant rejection and treatment of autoimmune diseases.

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Acknowledgements

This study was supported by research grants from the Canadian Institutes of Health Research (MOP 79415 and 89713).

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Author notes

  1. Haifeng Zhang and Yufeng Xie: These authors contributed equally to this work.

Authors and Affiliations

  1. Health Research Division, Department of Oncology and Immunology, Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Sask., Canada

    Haifeng Zhang, Yufeng Xie, Wei Li & Jim Xiang

  2. Health Research Division, Department of Pathology, Research Unit, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, Sask., Canada

    Rajni Chibbar

  3. Institute of Biology and Medical Sciences, Soochow University, Suzhou, China

    Sidong Xiong

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  1. Haifeng Zhang
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Correspondence to Jim Xiang.

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Zhang, H., Xie, Y., Li, W. et al. CD4+ T cell-released exosomes inhibit CD8+ cytotoxic T-lymphocyte responses and antitumor immunity. Cell Mol Immunol 8, 23–30 (2011). https://doi.org/10.1038/cmi.2010.59

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