Dendritic cells recruit T cell exosomes via exosomal LFA-1 leading to inhibition of CD8⁺ CTL responses through downregulation of peptide/MHC class I and Fas ligand-mediated cytotoxicity

Active T cells release bioactive exosomes (EXOs). However, its potential modulation in immune responses is elusive. In this study, we in vitro generated active OVA-specific CD8⁺ T cells by cultivation of OVA-pulsed dendritic cells (DC_OVA) with naive CD8⁺ T cells derived from OVA-specific TCR transgenic OTI mice and purified EXOs from CD8⁺ T cell culture supernatant by differential ultracentrifugation. We then investigated the suppressive effect of T cell EXOs on DC_OVA-mediated CD8⁺ CTL responses and antitumor immunity. We found that DCOVA uptake OTI T cell EXOs expressing OVA-specific TCRs and Fas ligand via peptide/MHC Ag I-TCR and CD54-LFA-1 interactions leading to downregulation of peptide/MHC Ag I expression and induction of apoptosis of DC_OVA via Fas/Fas ligand pathway. We demonstrated that OVA-specific OTI T cell EXOs, but not lymphocytic choriomeningitis virus-specific TCR transgenic mouse CD8⁺ T cell EXOs, can inhibit DC_OVA-stimulated CD8⁺ CTL responses and antitumor immunity against OVA-expressing B16 melanoma. In addition, these T cell EXOs can also inhibit DC_OVA-mediated CD8⁺ CTL-induced diabetes in transgenic rat insulin promoter-mOVA mice. Interestingly, the anti-LFA-1 Ab treatment significantly reduces T cell EXO-induced inhibition of CD8⁺ CTL responses in both antitumor immunity and autoimmunity. EXOs released from T cell hybridoma RF3370 cells expressing OTI CD8⁺ TCRs have a similar inhibitory effect as T cell EXOs in DC_OVA-stimulated CTL responses and antitumor immunity. Therefore, our data indicate that Ag-specific CD8⁺ T cells can modulate immune responses via T cell-released EXOs, and T cell EXOs may be useful for treatment of autoimmune diseases.