Anomalous killer cells are Thy-1(+) blasts that are cytolytic to the natural killer (NK)-sensitive lymphoma YAC-1, and that can be detected early (day 3-4) in the period preceeding the allospecific cytotoxic T lymphocyte (CTL) response in (CBA x A)F1 {arrow} C57B1 mixed leukocyte culture (MLC). We have investigated the origin and nature of anomalous killing (AK), with special emphasis on its relation to NK-and allospecific CTL-activity. AK was shown to be distinct from the previously described "NK(c)-cells" induced by cultivation in fetal calf serum (FCS)-supplemented medium when these two reactivities were examined in parallel. AK was detected in either FCS- or normal mouse serum (NMS)-supplemented allogeneic MLC, indicating that the response was not dependent on mitogenic or antigenic properties of heterologous serum. In addition to several H-2-incompatible combinations, AK was also observed in an Mls-incompatible (but H-2 compatible) and two F(1)- antiparental MLC responder/stimulator combinations. AK cells showed a similar selectivity pattern to NK cells, as demonstrated in cold target inhibition and direct cytotoxicity assays using variant or interferon-modulated YAC-1 cells with low expression of NK target structures. The AK-cells were NK- 1.2(-/weak). Thy-l.2(+), although they seem to be derived from non-adherent radiosensitive cells which are closely related, if not identical, to NK-cells (NK-1.2(+). Thy-l.2(-/weak)), as they could not be readily induced in responder populations with low NK-activity but normal allospecific CTL potential. Conversely, an in vivo thymectomy protocol or treatment of normal spleen cells with monoclonal anti-Thy-1.2 + C reduced the allospecific CTL response drastically but did not affect the AK response. Anomalous killers were not observed when MLC were prepared with responder as well as stimulator cells devoid of mature T cells. In such a combination, the AK response could be partially restored by the addition of irradiated +/nu (but not nu/nu) responder cells to the cultures. When normal (non-nude) spleen cells were used as responders, induction of AK did not require the presence of T cells in the stimulator population, whereas the removal of adherent and phagocytic cells from stimulators abrogated the response. Taken together, the results suggest that AK represents activation, blast transformation, and surface marker modulation of NK cells induced by alloantigen-stimulated T cells, resulting in Thy-1(+) cytolytic cells with similar properties to those described for NK lines, Although AK cells may be regarded as a more T cell-like NK phenotype, their induction is neither necessary, nor sufficient for generation of specific CTL in MLC.

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