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 DC(OVA) 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.
Xie
Yufeng
Y
Division of Health Research, Saskatchewan Cancer Agency, Saskatchewan, Saskatoon, Canada.
Zhang
Haifeng
H
Li
Wei
W
Deng
Yulin
Y
Munegowda
Manjunatha Ankathatti
MA
Chibbar
Rajni
R
Qureshi
Mabood
M
Xiang
Jim
J
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D055354:Exosomes / Q000276:immunology* / Q000648:ultrastructure; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides; D051381:Rats; D015398:Signal Transduction; D014461:Ultracentrifugation
D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I; D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D010047:Ovalbumin