Dominance of tissue-restricted cytotoxic T lymphocytes in the response to allogeneic renal epithelial cell lines.

Abstract

Our current knowledge of cytotoxic T lymphocytes (CTL) is largely derived from studies of effector populations generated in allogeneic mixed leukocyte cultures (MLC) and assayed for lytic activity to lymphoid cell (LC) targets. We herein report that the CTL response to allogeneic renal epithelial cell lines (REC) is dominated by effectors that efficiently lyse REC targets but show little cross-reactivity with LC targets. In contrast, CTL generated against allogeneic spleen cell stimulators (ie., in MLC) lysed REC and LC targets at comparable levels. Lytic activity in both types of cultures was mediated by CD8+TCRalpha/beta+ cells directed to classical H2 class I alloantigens. Anti-REC effectors cross-reacted with fibroblast and macrophage targets but not with targets commonly used to detect alloreactive CTL, such as lipopolysaccharide- or Con A-stimulated lymphoblasts or lymphoid tumor lines, whereas MLC-elicited effectors efficiently lysed all targets. CTL clones propagated from anti-REC cultures exhibited the same allospecificity and tissue specificity as bulk anti-REC effectors. Individual CTL clones were highly heterogeneous in their capacity to recognize the same class I alloantigen expressed on cells derived from different tissues. These data demonstrate that the cellular environment in which CD8 precursors encounter class I alloantigens can have a profound effect on the cell-type specificity of CTL populations. An important implication of these data is that conventional assays of CTL lytic activity may fail to reveal a significant component of the host response to allogeneic tissues.