SUPPORTIVE CELLULAR-ELEMENTS FOR HEPATIC T-CELL DIFFERENTIATION - T-CELLS EXPRESSING INTERMEDIATE LEVELS OF THE T-CELL RECEPTOR ARE CYTOTOXIC AGAINST SYNGENEIC HEPATOMA, AND ARE LOST AFTER HEPATOCYTE DAMAGE

Extrathymic T cells exist in the liver and are often seen in close con tact with Kupffer cells in the hepatic sinusoids. Since selective depl etion of Kupffer cells has became possible by using liposome-encapsula ted clodronate, it was investigated whether elimination of Kupffer cel ls influences the level of extrathymic T cells in the liver. Extrathym ic T cells were identified as interleukin-2 receptor beta-chain (IL-2R beta) intermediate TCR (TCR(int)) cells by two-color staining for CD3 or T cell receptor (TCR) and IL-2R beta. The elimination of Kupffer c ells did not significantly affect levels of TCR(int) cells up to 7 day s after treatment. We then examined monocyte colony stimulating factor (M-CSF)-deficient op/op mice (low levels of Kupffer cells). Extrathym ic T cells both in the liver and spleen of these mice were detected at a level comparable to that of control mice. Since extrathymic T cells in the liver are sometimes located in the parenchymal space, the rela tionship between extrathymic T cells and hepatocytes was then examined . Electron microscopy revealed that some hepatic T cells adhered direc tly to hepatocytes. When hepatocytes were damaged by a single injectio n of CCl4, hepatocyte death and subsequent hepatic fibrosis were induc ed. Beginning 3 days after injection, CD3(int) cells, but not other ty pe of cells, decreased prominently. Purified CD3(int) cells, as well a s whole lymphocytes in the liver, were cytotoxic against syngeneic hep atoma. In parallel with the above-mentioned hepatic damage, the cytoto xic activity of lymphocytes against such targets was impaired in the l iver. These results suggest that extrathymic generation of TCR(int) ce lls and their acquisition of cytotoxic function are relatively indepen dent of Kupffer cells, but are dependent on hepatocytes.