Human liver-associated lymphocytes: an overview

Morphological and phenotypical data indicate that liver sinusoids contain a heterogeneous population of lymphocytes of which large granular lymphocytes are only one element. It is suggested that the term of liver-associated lymphocytes (LAL), which encompasses all sinusoidal lymphocytes, be used for this fourth sinusoidal cell type. Studies realized by flow cytometry on isolated cells have shown that human LAL differ phenotypically from peripheral blood lymphocytes (PBL). LAL are characterized by a three-fold increase in the percentage of cells presenting the CD56 antigen, a natural killer (NK) marker, but also an increase in the percentage of CD8 cells and a decrease in the percentage of CD4. Furthermore, within the CD56+ LAL population, 95% of cells are CD3+/- CD16-, whereas the majority of CD56+ cells in PBL are CD3-/CD16+. These differences do not seem to depend on liver pathology since no differences were found in the LAL phenotype, for all markers analysed, between patients with liver metastasis or with benign liver tumours. Liver sinusoids also harbour T cells bearing the gamma/delta chains with a repertoire of V gene arrangements which differs from that found in PBL from the same patients, confirming a site-specificity. Functionally, LAL were shown to possess a higher level of NK cell activity against K-562 cells than PBL. LAL also expressed a lymphokine activated killer (LAK) activity against NK-resistant cell lines (Raji cells), whereas no such activity was detected in PBL from the same patients. Interestingly, LAK-activity from LAL isolated from patients with liver metastases was dramatically decreased compared to that from LAL isolated from patients with benign liver disease. The level of LAK activity of LAL situated distant to the malignant tumour was higher than that obtained from LAL close to the tumour, thus suggesting that cytotoxic lymphocyte capabilities could be inhibited by tumoral cells. LAL differ, both quantitatively and qualitatively, from PBL in the expression of cellular adhesion molecules. Precise mechanisms of their homing or in situ differentiation must still be elucidated.