Immunology of the healthy liver: Old questions and new insights

The immunologic properties of the liver confront one with a combination of unique phenomena. These include graft survival across major histocompatibility antigen disparities, induction of systemic tolerance to food antigens, persistence of some viral infections for decades, and a collection of liver-specific immune-mediated diseases. 1‐ 4 The immunologic basis for these phenomena has been an active area of research, but in contrast the immunology of the healthy liver has received little attention. In this review the following questions will be addressed: what is the relationship of the healthy liver with the immune system? Does the liver have a unique immunologic function on a daily basis, and can an understanding of this provide insights into the liverspecific phenomena listed above? This review will summarize the current information on the immune functions of the healthy liver, and present some hypotheses on why these functions can be expected to give the liver a unique immunologic role in medical therapeutics and disease. Histologic study of the liver identifies liver-specific cell populations such as Kupffer cells and stellate cells, but does not suggest that there are many immunologically relevant cells present. 5 When the liver is digested and the nonparenchymal cells are characterized, a very different picture emerges. As early as 1976, “lymphoid” cells were shown to comprise 16%‐22% of the nonparenchymal cell pool, and this has subsequently been confirmed. The absolute number of lymphocytes in liver tissue is in the range of 10 ‐20 million cells per gram of tissue. 6 The high concentration of lymphocytes and the size of the liver results in a total hepatic lymphocyte number of 15%‐20% of the lymphoid cells in the spleen. This is a remarkable status for a nonlymphoid organ. The liver lymphocyte population is very diverse. Lymph nodes and the spleen are comprised primarily of B cells and T cells with the ab receptor (TCRab), the most common T cell in the body. The vast majority of TCRab cells remain as resting naive cells unless their TCR is activated by peptide antigen bound to either class I or class II major histocompatibility complex (MHC) molecules (class I for CD8 1 T