Enhanced suppression of polyclonal CD8+25+ regulatory T cells via exosomal arming of antigen-specific peptide/MHC complexes
-
- Chuanyong Mu
- Department of Respiratory Medicine, The First Affiliated Hospital, Soochow University , Soochow , China
-
- Xueshu Zhang
- Cancer Research Department, Saskatchewan Cancer Agency, University of Saskatchewan , Saskatoon, Saskatchewan , Canada
-
- Lu Wang
- Cancer Research Department, Saskatchewan Cancer Agency, University of Saskatchewan , Saskatoon, Saskatchewan , Canada
-
- Aizhang Xu
- Cancer Research Department, Saskatchewan Cancer Agency, University of Saskatchewan , Saskatoon, Saskatchewan , Canada
-
- Khawaja Ashfaque Ahmed
- Cancer Research Department, Saskatchewan Cancer Agency, University of Saskatchewan , Saskatoon, Saskatchewan , Canada
-
- Xueqin Pang
- Department of Respiratory Medicine, The First Affiliated Hospital, Soochow University , Soochow , China
-
- Rajni Chibbar
- Department of Pathology, University of Saskatchewan , Saskatoon, Saskatchewan , Canada
-
- Andrew Freywald
- Department of Pathology, University of Saskatchewan , Saskatoon, Saskatchewan , Canada
-
- Jianan Huang
- Department of Respiratory Medicine, The First Affiliated Hospital, Soochow University , Soochow , China
-
- Yehan Zhu
- Department of Respiratory Medicine, The First Affiliated Hospital, Soochow University , Soochow , China
-
- Jim Xiang
- Cancer Research Department, Saskatchewan Cancer Agency, University of Saskatchewan , Saskatoon, Saskatchewan , Canada
抄録
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
収録刊行物
-
- Journal of Leukocyte Biology
-
Journal of Leukocyte Biology 101 (5), 1221-1231, 2017-01-17
Oxford University Press (OUP)