Enhanced suppression of polyclonal CD8+25+ regulatory T cells via exosomal arming of antigen-specific peptide/MHC complexes

Abstract

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.

Orally Administered Exosomes Suppress Mouse Delayed-Type Hypersensitivity by Delivering miRNA-150 to Antigen-Primed Macrophage APC Targeted by Exosome-Surface Anti-Peptide Antibody Light Chains

“…However, this has often been tested only in one-way Ag-activity system by simple comparison to challenge with another Ag or just media, or testing non-immune hosts with the involved Ag, as controls. Thus, the mechanisms in these studies should instead be considered only Ag-dependent [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Furthermore, the Ag-specificity of the function of other suppressive exosomes was not established in the important and meticulous study of RNAs involved in the suppression of Th1 cells by classical FoxP3 + Treg cells [ 25 ], and in another study on immunopathogenesis mediated by Treg cell-derived EVs [ 29 ].…”

The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers

“…CD4+CD25+Foxp3+ Tregs exert their non-specific immune suppression via modulating either T-cells or antigen presenting cells (APCs) in a cell‐to‐cell contact-dependent manner by producing inhibitory cytokines, including IL-10 and transforming growth factor beta (TGF-β) [ 72 ]. In fact, AZD6738, a ATR inhibitor (ATRi), reportedly correlates with Treg infiltration in lung cancer and colorectal cancer murine models [ 51 , 73 ].…”

Antiangiogenesis Roles of Exosomes with Fei‐Liu‐Ping Ointment Treatment are Involved in the Lung Carcinoma with the Lewis Xenograft Mouse Model

“…between cells [18]. Exosomes can enter the lymphatic system and capillaries within the tumour tissue and play roles in immune evasion and the regulation of T cells and NK cells [19,20]. e exosomes interact with tumour suppressors and participate in the regulation of tumour growth [21].…”