Physiological responses of extrathymic T cells in the liver

Abstract

The liver has been found to be one of the important hematopoietic organs even after birth. Namely, adult liver still comprises c-kit+ stem cells and gives rise to extrathymic T cells, natural killer (NK) cells, and even granulocytes. Extrathymic T cells generated in the liver of mice are intermediate T-cell receptor (TCR(int)) cells, including the NK1.1+TCR(int) (i.e. NKT cells) and NK1.1-TCR(int) subsets. Although extrathymic T cells are few in number in youth, they gradually increase in number with aging. Even in youth, the number and function of extrathymic T cells are elevated under conditions of stress, infection, malignancy, pregnancy, autoimmune disease, chronic graft-versus-host diseases, etc. Under these conditions, the mainstream of T-cell differentiation in the thymus, which produces conventional T cells, is rather suppressed. Since extrathymic T cells comprise self-reactive forbidden clones and mediate cytotoxicity against abnormal self-cells (e.g. malignant tumor cells, microbially infected hepatocytes, and regenerating hepatocytes), they are beneficial for the elimination of such cells. However, overactivation or continuous activation of extrathymic T cells might be harmful and responsible for the onset of autoimmune diseases. We finally propose the possibility that switching of the immune system from the thymus to the liver might be regulated by the autonomic nervous system as well as by cytokines.

Increase in Hepatic NKT Cells in Leukocyte Cell-Derived Chemotaxin 2-Deficient Mice Contributes to Severe Concanavalin A-Induced Hepatitis

“…There is growing evidence that NKT cells play an important role in immune responses (9 -13). It is well established that NKT cells express large amounts of cytokines, especially IFN-␥ and IL-4, and their functional disorders are characteristic of various diseases (9,12,13). Recently, some groups reported that NKT cells played an essential role in Con A-induced hepatitis (14 -16).…”

Extrathymic TCR Gene Rearrangement in Human Small Intestine: Identification of New Splice Forms of Recombination Activating Gene-1 mRNA with Selective Tissue Expression

“…T cell development mainly occurs in the thymus but can also take place outside this organ. In mice, small intestinal mucosa and liver are suggested sites for extrathymic T cell maturation (ETCM) (5)(6)(7). Lymphocyte clusters located adjacent to the crypts in the intestinal lamina propria (LP), so called cryptopatches, were shown to be the sites for progenitor cells in ETCM yielding T cells that populate the intestinal epithelium (6,8).…”

Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver

“…A second mechanism by which pretreatment with AdsDR5 may inhibit liver cell apoptosis after AdCMVLacZ treatment is by inhibition of NK cell activation and production of cytokines including IFN-␥. Several investigators (1,8,28,35,39) have shown that NK cells are a relatively rare cell population in peripheral lymphoid organs but are abundant in the liver. An initial response to viral infection primarily involves the innate arm of the immune response resulting in killing of infected cells by NK cells.…”