Compared with CD425 regulatory T cells (T), the mechanisms for natural, polyclonal CD825 T 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 CD825 T or CD825 T armed with ovalbumin (OVA)-specific exosomes on other immune cells and OVA-specific dendritic cell (DC)-stimulated antitumor immunity. We demonstrate that CD825 T 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. CD825 T anergize naïve T cells upon stimulation by up-regulating T cell anergy-associated and down-regulating IL-2 production. T also anergize DCs by preventing DC maturation through the down-regulation of Ia, CD80, CD86, and inflammatory cytokines, leading to defects in T cell stimulation. Moreover, CD825 T 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 CD825 T suppress DC-stimulated CTL responses in priming and effector phases and inhibit immunity against OVA-expressing CCL lung cancer. Remarkably, polyclonal CD825 T 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 CD825 T for enhanced immune suppression can be achieved through exosomal pMHC arming. This principle may have a great effect on T-mediated immunotherapy of autoimmune diseases.