Interstitial liver dendritic cells (DCs) exhibit phenotypic diversity and functional plasticity. They play important roles in both innate and adaptive immunity. Their comparatively low inherent T cell stimulatory ability and the outcome of their interactions with CD4 ุ and CD8 ุ T cells, as well as with natural killer (NK) T cells and NK cells within the liver, may contribute to regulation of hepatic inflammatory responses and liver allograft outcome. Liver DCs migrate in the steady state and after liver transplantation to secondary lymphoid tissues, where the outcome of their interaction with antigen-specific T cells determines the balance between tolerance and immunity. Systemic and local environmental factors that are modulated by ischemia-reperfusion injury, liver regeneration, microbial infection, and malignancy influence hepatic DC migration, maturation, and function. Current research in DC biology is providing new insights into the role of these important antigen-presenting cells in the complex events that affect liver transplant outcome. (HEPATOLOGY 2007;46:2021-2031.)
A lthough well-recognized as a potential site of inflammatory disease, the liver also displays inherent tolerogenic properties, as evidenced by its role in oral tolerance and the comparative immune privilege of hepatic allografts. "Spontaneous" acceptance of liver transplants, in the absence of immunosuppressive therapy, was demonstrated initially in outbred pigs, 1 then across major histocompatibility complex (MHC) barriers in mice 2 and in some rat strain combinations. 3 In humans, liver transplants confer protection on other organ grafts from the same donor. 4 Further, experimental liver transplantation can induce systemic, donor-specific tolerance. 5 There are many distinctive immunologic features of the hepatic environment, 6 including a constituency of various antigen (Ag)-presenting cells (APCs) and locallyproduced factors that can regulate immune responses.
Resident APCs within the liver include both leukocytes (Kupffer cells [KCs] and dendritic cells [DCs]) and parenchymal cells, that is, sinusoid-lining endothelial cells, hepatocytes, and stellate (Ito) cells. These APCs occupy distinct functional niches and may display functional plasticity with ability to instigate immune responses or promote tolerance. Here, we focus on aspects of liver DC biology that relate to their roles in the induction and regulation of innate and adaptive immunity, and in liver transplant outcome. Many factors affect liver DC recruitment, maturation, function, and migration, and likely include anti-inflammatory and immunosuppressive agents (Fig. 1). 7
DC Phenotype, Diversity, and Plasticity
DCs are rare, ubiquitously distributed leukocytes, derived from CD34 ฯฉ hematopoietic stem cells. 8 In normal liver, they are restricted largely to the perivenular region, portal space, and beneath the Glisson capsule, with a few cells scattered throughout the parenchyma 9,10 (Fig. 2A). The cytokines fms-like tyrosine kinase 3 ligand (Flt3L) and granulocyte macrophage colony-stimulating factor (GM-CSF) mobilize DCs from bone marrow. They can be used to enrich DCs in the liver (Fig. 3), 11 enhancing the feasibility of liver DC studies. DCs can also be propagated from liver nonparenchymal cells 12 (Fig. 2B-D).
Various cell surface markers have been employed to identify and purify rodent, nonhuman primate, and human DCs (Table 1). [13][14][15][16][17][18][19][20][21][22][23] CD11c is a very useful marker of DCs in mice. Other Ags, such as the mannose receptor CD205 (formerly DEC205), can help identify mouse