PROFOUND SUPPRESSION OF THE DIFFERENTIATION AND FUNCTIONS OF INTERMEDIATE TCR CELLS IN THE LIVER OF MICE WITH LIVER-INJURY INDUCED BY CARBON-TETRACHLORIDE

The immunologic states of mice with acute liver injury and subsequent chronic liver fibrosis, which were induced by continuous administrations of CCl4, were investigated. At an early phase of induction (3 days and 1 week after the initiation), the numbers of mononuclear cells yielded by the liver, thymus and spleen decreased prominently, and activities of aspartate aminotransferase and alanine aminotransferase in sera were elevated. A most striking change revealed by the phenotypic characterization at this time was a selective decrease in the proportion and the absolute number of intermediate TCR cells in the liver. This feature continued during the chronic phase of liver fibrosis. These intermediate TCR cells of extrathymic origin in the liver constitutively expressed IL-2 receptor beta-chain similar to NK cells and contained double-negative CD4(-)8(-) cells. In the early phase, the level of CD3(-)IL-2R beta(+) cells (mainly NK cells) also decreased slightly in the liver, whereas that of bright TCR cells remained unchanged in the liver and other organs. The proportion of gamma delta T cells, which were previously shown to belong to the intermediate TCR cells, in the liver also decreased. Decreased mRNA levels of recombination activating gene-1 (RAG-1) and RAG-2 genes were seen in hepatic mononuclear cells in mice with acute liver injury. The cytotoxic function of intermediate TCR cells was profoundly impaired in these mice, These results suggest that the most sensitively affected lymphocyte subsets in case of liver injury are the intermediate TCR cells in the liver and that intact microenvironments of the liver are important for supporting their differentiation and functions.