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The role of non-H-2 alloantigens, specifically Mls locus products, in secondary in vitro T-cell-mediated cytotoxicity has been studied. Splenic T lymphocytes, activated against Mls locus alloantigens in primary-mixed cultures and isolated by velocity sedimentation gradient separation techniques, were used as responding populations in secondary mixed leukocyte cultures (MLCs) and cell-mediated lympholysis (CML). Such T-cell clones could be shown to exhibit either "self"-H-2-restricted or anti-Mls locus-specific reactivity, with this dichotomy of reactivity depending only on the primary culture conditions. Mls locus-activated T lymphocytes generated in cultures supplemented with homologous serum exhibited specific memory responses in MLC, yet remained incapable of effecting target cell destruction against Mls locus antigens or against "self"-H-2-structures in CML. In contrast, activated T-cell clones generated in the presence of heterologous serum displayed H-2-restricted reactivity in both secondary MLC and CML. H-2-restricted MLC activation was controlled by products of the H-2 serologically defined regions. Although heterologous serum was a necessary (and sufficient) entity for development of H-2-restricted responses, evidence argues against the possibility that heterologous serum acts via modification of cell surface components.

A stable variant of a clone of the P388D1 macrophage line was isolated using four cycles of treatment with mouse IgG2a-rabbit anti-kappa complexes and rabbit complement. The variant had the same Ka and about the same number of sites per cell for IgG2a as the parent line. However, the variant had 10% as many binding sites for rabbit IgG in soluble antigen-antibody complexes, and the affinity of binding was threefold higher. This change in binding of complexes to cells of a cloned line without alternation of IgG2a binding provides evidence for the presence of two distinct Fc receptors. The two receptors could also be distiguished on the P388D1 line and on thioglycollate-induced mouse peritoneal macrophages by differential sensitivity to trypsinization. The receptors that bind monomeric IgG2a, sheep erythrocytes (SRBC) covalently bound with IgG2a or rabbit IgG using glutaraldehyde, and Sephadex beads coupled with IgG2a or rabbit IgG using cyanogen bromide activitation, is sensitive to trypsinization. The receptor that binds soluble rabbit antibody-antigen complexes, trinitrophenyl-SRBC and dinitrophenyl(DNP)-bovine serum albumin Sephadex beads coated with rabbit anti-DNP IgG is trypsin resitant, the observation that uncomplexed rabbit IgG oes not bind to the trypsin-resistant receptor, whereas the same IgG bound to its antigen does, suggests that conformational changes induced by the binding of ligand may be of consequence in macrophage function.

We have shown that the selective removal of cells possessing Ia determinants coded by the I-A, I-B, and I-J regions of the H-2 gene complex completely abrogates the protective capacity of nylon-wool-purified T lymphocytes against leukemic challenge. This suggests that the Ia antigen bearing T cells play an important role in tumor immunity.

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