The ultraviolet radiation-induced fibrosarcoma 1591 generally is rejected by normal syngeneic mice and only rarely exhibits progressive growth. We isolated five of these rare progressor tumors from normal animals to determine the selective pressures that had been exerted upon the parental tumor by normal immunocompetent hosts. We found that the variant tumor cell lines could neither induce nor be killed by tumor-specific lymphocytes, suggesting that selection had been exerted against tumor cells expressing the tumor-specific antigen. In contrast, no selection against natural killer cell activity or against nonspecific T cell-mediated immunity seems to have occurred because progressor tumor cells were highly sensitive to these types of effector cells and in fact induced these effector cells more effectively than did the parental tumor. Nude mice were found to be as capable as normal mice in generating natural killer activity in response to a challenge with progressor tumor cells, but they were unable to mount a nonspecific T lymphocyte response. This may account for the fact that the progressor tumors grew at a significantly faster rate in nude animals than in normal mice. Thus, our study shows that in this tumor system nonspecific T cell-mediated immunity may play a role in retarding tumor growth, but the absolute resistance of normal animals to progressive tumor growth critically depends upon the presence of T cell-mediated tumor-specific immunity. Furthermore, neither NK cells nor nonspecific cytotoxic T lymphocytes appear to play a role in immunoselection against this tumor in normal immunocompetent hosts.
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.
Summary A mouse IgGi monoclonal antibody (1C4), which recognizes a cell surface molecule on murine natural cytotoxic{NC) cells was produced. By flowcytometry. IC4preferentially reacted with less than 5% of fresh CBA spleen cells and 20-50% of CBA-interleukin-3 (lL-3) cells, an in vitro derived NC-like cell line. In vitro treatment of spleen cells from a number of inbred mouse strains either with 1C4 alone or 1C4 coupled to dynabeads markedly decreased or abolished NC activity of the cells against ^'Cr-labelled WEHl-164 targets. Splenic NC activity of these same mouse strains was also reduced or abolished by in vivo administration of IC4. The effect was evident within 2 h of treatment and persisted for at least I week. In contrast IC4 had little or no effect on splenic NK activity against "Cr-labeiled YAC-I targets over the same range of experiments in vitro and in vivo. Results of strain surveys for both in vitro and in vivo reduction of splenic NC activity by 1C4 treatment showed that CBA. C57BL/6, BALB/c and NZB mice were positive and CE and DBA/2 mice were negative, indicating that 1C4 recognizes an allo-antigen on mouse NC cells. This allo-antibody has been designated NC-II, and thus IC4 is an anti-NC-11 monoclonal antibody.
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