JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
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Enhanced suppression of polyclonal CD8 + 25 + regulatory T cells via exosomal arming of antigen-specific peptide/MHC complexes.

Compared with CD4+ 25+ regulatory T cells (Tregs ), the mechanisms for natural, polyclonal CD8+ 25+ Treg immune suppression have been significantly less studied. We previously showed that polyclonal T cells can acquire antigen-specific targeting activity through arming with exosomal peptide-MHC (pMHC). In this study, we assessed the suppressive effect of CD8+ 25+ Tregs or CD8+ 25+ Tregs armed with ovalbumin (OVA)-specific exosomes on other immune cells and OVA-specific dendritic cell (DCOVA )-stimulated antitumor immunity. We demonstrate that CD8+ 25+ Tregs inhibit T cell proliferation in vitro in a cell contact-dependent fashion but independent of the expression of immunosuppressive IL-10, TGF-β, and CTLA-4. CD8+ 25+ Tregs anergize naïve T cells upon stimulation by up-regulating T cell anergy-associated Egr2 and down-regulating IL-2 production. Tregs also anergize DCs by preventing DC maturation through the down-regulation of Iab , CD80, CD86, and inflammatory cytokines, leading to defects in T cell stimulation. Moreover, CD8+ 25+ Tregs inhibit CTLs through inducing CTL death via perforin-mediated apoptosis and through reducing effector CTL cytotoxic activity via down-regulating CTL perforin-production and degranulation. In addition, we show that CD8+ 25+ Tregs suppress DCOVA -stimulated CTL responses in priming and effector phases and inhibit immunity against OVA-expressing CCLOVA lung cancer. Remarkably, polyclonal CD8+ 25+ Tregs armed with OVA-specific exosomal pMHC class-II (pMHC-II), or pMHC class-I (pMHC-I) complexes exert their enhanced inhibition of CTL responses in the priming and the effector phases, respectively. Taken together, our investigation reveals that assigning antigen specificity to nonspecific polyclonal CD8+ 25+ Tregs for enhanced immune suppression can be achieved through exosomal pMHC arming. This principle may have a great effect on Treg -mediated immunotherapy of autoimmune diseases.

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