Hybrid resistance to parental H-2b bone marrow grafts is directed to a cell surface structure controlled by the Hh-1 locus in or near the H-2D region. The nature of this surface structure is not known. Since homozygosity at the class I H-2D locus or loci in this haplotype would seem a necessary but not sufficient condition for the grafts' susceptibility to resistance, we tested whether the expression of this phenotype is dependent on the expression of class I H-2Db determinants. Cloned variants of H-2b tumor RBL-5 were obtained by immunoselection for the absence of H-2Db expression, as determined by the inability to bind specific antibody and to induce or react with alloreactive cytotoxic T lymphocytes. The three clones used in this study were H-2Db negative but H-2Kb positive and were natural killer cell resistant. When tested in vivo as competitive inhibitors the variant cells were capable of blocking hybrid resistance to parental H-2b bone marrow grafts as were unselected H-2Db-positive parental line cells. Therefore, H-2Db expression is irrelevant for Hh-1b expression. An incidental observation was that YAC-1 cells, a non-H-2b tumor with pronounced susceptibility to natural killing, were able to block hybrid resistance. This reactivity, not observed in our previous studies, raises the possibility that at least some of the effector cells are cross-reactive or capable of dual recognition.

Administration of a single dose of C. parvum (CP) induces depression of splenic NK activity in mice after a lag period of 3-5 days and this depression lasts about 2 weeks. The depressed levels of NK activity noted in this study depended on time of CP administration and were associated with the induction of suppressor cell activity. Neonatally thymectomized or sublethally irradiated mice had unimpaired ability to generate suppressor cells following CP treatment. Depletion of adherent/phagocytic cells by carbonyl iron plus magnetism, Sephadex G-10 filtration, or both neither enriched NK activity nor removed suppressor activity from the spleens of CP-treated mice. Antibody-dependent cellular cytotoxicity (ADCC) against lymphoma targets was also depressed in CP-treated mice, accompanied by a concomitant appearance of suppressor cells that interfere with ADCC at the effector level.

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Hybrid resistance (HR) is primarily controlled by the genes of the Hemopoietic histocompatibility-1 (Hh-1) locus within the H-2 complex. HR is a consequence of the Hh-1-controlled target determinants in homozygous parental strain mice and their absence in heterozygous F1 hybrid mice. To examine the mechanism that controls the Hh-1 phenotype, three independent clones of somatic cell hybrids between parental lines EL-4 (C57BL/6 origin, H-2b) and R1 (C58 origin, H-2k) were studied. The line EL-4 is Hh-1b-positive and is subject to HR by H-2b heterozygous F1 mice, but R1 lacks the Hh-1b allele and is not susceptible to HR. Of the three hybrid clones, F263.2 is Hh-1b-positive, whereas the other two, F262.2 and F264.2, are Hh-1b-negative, as judged by these cells' capacity to compete in vivo with the grafted parental C57BL/6 bone marrow cells in the resistant (C57BL/6 x C3H)F1 mice. All three clones express the H-2b and H-2k class I antigens equally well, are susceptible to activated NK cells to the same extent, and all carry four copies of chromosome 17. However, Southern analysis reveals that clone F263.2 contains three copies of H-2b chromosome and one H-2k, whereas the other two clones carry two copies each of the parental chromosome 17. The results suggest that the relative copy number of specific alleles is the crucial determinant of the Hh-1 phenotype, and render unlikely both the gene dosage hypothesis and the trans-acting dominant suppression hypothesis to account for the noncodominant expression of the Hh-1 phenotype.