Graft‐infiltrating PD‐L1hi cross‐dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance

Abstract

These findings suggest that graft-infiltrating PD-L1 CD-DCs may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. (Hepatology 2018;67:1499-1515).

DNAX Activating Protein of 12 kDa/Triggering Receptor Expressed on Myeloid Cells 2 Expression by Mouse and Human Liver Dendritic Cells: Functional Implications and Regulation of Liver Ischemia–Reperfusion Injury

“…Liver‐resident antigen (Ag)–presenting cells (APCs) of hematopoietic and nonhematopoietic origin, which have been shown to regulate inflammatory and T cell–mediated immune responses, include dendritic cells (DCs), Kupffer cells, sinusoid‐lining endothelial cells, and hepatic stellate cells. In particular, liver DCs, which are regarded as critical instigators and regulators of innate and immune‐mediated inflammatory responses, have been implicated in control of acute liver injury, T cell–mediated and autoimmune hepatitis, and the promotion of oral and transplant tolerance.…”

Maintaining T cell tolerance of alloantigens: Lessons from animal studies

“…In mice, these allografts are often accepted without requirement for immunosuppressive therapy (61). The immune privilege status of the liver is associated with the presence of resident professional and nonprofessional APCs, including DCs and hepatic macrophages (Kupffer cells) (62–64), liver sinusoidal endothelial cells (LSEC) (65), hepatic stellate cells (66), and hepatocytes (67). Liver DCs are characterized by their immaturity (68, 69) and tolerogenic properties (70–72).…”

“…A recent study from Thomson’s laboratory supported the role of antigen cross-dressing in mouse spontaneous liver transplant tolerance. They reported that the majority of recipient DCs found in accepted liver allografts were cross- dressed with donor MHC class I expressing high levels of PD-L1 and IL-10 as compared with non–cross-dressed-DCs isolated from the graft (64). Concurrently, graft- infiltrating T cells displayed PD-1 and TIM-3, which are features of exhausted cells, on their cell surface (64).…”

“…They reported that the majority of recipient DCs found in accepted liver allografts were cross- dressed with donor MHC class I expressing high levels of PD-L1 and IL-10 as compared with non–cross-dressed-DCs isolated from the graft (64). Concurrently, graft- infiltrating T cells displayed PD-1 and TIM-3, which are features of exhausted cells, on their cell surface (64). Therefore, as shown in NIMA tolerant mice, maintainance of liver transplant tolerance appears to involve continuous transfer of donor MHC from hematopoietic and liver parychymal or stromal cells and subsequent cross-dressing of DCs and/or other recipient APCs expressing co-inhibitory receptors and secreting anti- inflammatory cytokines.…”

Peacekeepers are cross‐dressed in the liver land

“…More recently, they have used CD11c‐diphtheria toxin receptor donors to document that myeloid DCs are essential for liver tolerance induction. The current work in this issue of H epatology not only extends in‐depth exploration of the tolerogenic mechanisms of hepatic DCs but also illuminates a new aspect in transplant immunology, i.e., cross‐dressing in recipients' APCs.…”