SUMMARYWe have studied the role of three mouse distinct non-H-2 genes (Bcg, Tbc-1, xid ) in several phenomena of antituberculosis immunity and resistance. On the basis of median survival time (MST) of mice following infection with virulent Mycobacterium tuberculosis H37Rv, Bcg gene did not control resistance to the lethal dose of H37Rv infection in non-vaccinated and Myco. bovis (BCG)-vaccinated mice. However, Bcg r allele, in comparison with Bcg s allele, determined more effective suppression of an early multiplication in spleens of H37Rv mycobacteria after a low dose (5 2 10 4 colony-forming units (CFU)) injection. CBA/N mice, which are not protected efficiently against tuberculous challenge by BCG vaccination, were characterized by a decreased in vitro proliferation of immune lymph node cells, both spontaneous and stimulated with mycobacterial antigens. The decreased proliferation was due to immunosuppression caused by interactions between responding T cells and CBA/N antigen-presenting cells (APC). We have confirmed that the defective response to BCG-vaccination in CBA/N mice is linked with the X-chromosome and thus is presumably determined by the xid gene itself. I/St mice (Tbc-1 s ), supersusceptible to H37Rv infection, were not able to restrict the growth of H37Rv mycobacteria in spleens, even following infection with a low dose (5 2 10 4 ), but restricted the growth of Myco. bovis BCG more effectively than Bcg s mice.

SUMMARYWe have studied the impact of distinct haplotypes and of difTerent alleles at specific H-2 loci on: (i) the susceptibility to lethal form of experimental tubereulosis; (ii) the level of DTH to mycobaclerial antigens; (iii) the efficacy of vaccination wilh bacille Calmette-Gucrin (BCG); and (iv) the IgG production and Tcell proliferative response to H37Rv antigens. On lhe basis of median survival lime (MST) following primary inoculation wilh lethal dose of Myeobaeterium tutwrcidosis, susceptibility to infection associated with I-A'' and // alleles. host resistance associaled with /-/I* and D'' alleles. Mice bearing a disease-resistant phenotype also developed a vigorous DTH response. Vaccination with BCG before H37Rv infection significantly prolonged the .survival time of both resistant and susceptible animals, except in BIO.M (H-2') mice. The latter exhibited intermediate resistance to infection before but slight decrease in lhe MST following a high-dose BCG vaccination. Distinct H-2 regulation of su.sceptibility to lethal infection and of BCG vaccination efiicacy was confirmed in another relatively resistant //-^'-bearing strain A.CA,, in which mortality occurred more rapidly in vaccinated compared with primarily infected animals. The expression of the H-2' haplotype was associated wilh a low DTH response to tuberculin following vaccination and subsequent lethal infection. The lack of BCG protection against Myco. tubercutosis QhaWcnofi'uy BIO.M mice associated with the high titre of specific IgG, In addilion, these mice exhibited a unique ability to respond to65-kD aniigen by both IgG synthesis and T cell proliferation.

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SUMMARYIt is firmly established that the allelic composition of the H-2 complex has a prominent impact on the course of tuberculosis (TB) infection in mice, including granuloma formation, mycobacterial spread in the lungs, and the dynamics of mortality. Although intuitively obvious, the role of long-term specific T cell responses in the expression of corresponding phenotypes is poorly understood. In this study we have compared polyclonal lymph node cell response (cell yield, proliferation, surface markers, IL-4/ interferon-gamma (IFN-g) production) to Mycobacterium tuberculosis H37Rv sonicate in repeated 10-day cycles of stimulation/rest between H-2 congenic IE-negative mouse strains, categorized on the basis of mortality following lethal challenge as TB-susceptible (C57Bl/6), TB-resistant (4R) and BCG non-protected (B10.M). The capacity to retain specific responsiveness to repeated stimulation by mycobacterial antigens depended upon both the H-2 haplotype of the host and the immunizing dose of the antigen. 4R lymph node cells following either 50 mg/mouse or 100 mg/mouse immunization constantly responded to sonicate, increased in numbers, and after the third stimulation/rest cycle developed into a stable CD3 þ CD4 þ cell line. B6 cells following either 50 mg/mouse or 100 mg/mouse immunization, and B10.M cells following 100 mg/mouse (but not 50 mg/mouse) immunization, lost the capacity to incorporate methyl-3 H-thymidine during the second cycle, and died. Analogous results were obtained in the in vivo experiments, when the dynamics of the response over 12 weeks following a single immunization with the antigen was studied. In response to the antigen, cells from all three mouse strains produced significant amounts of IL-2 and IFN-g, but not IL-4, indicating that they belong predominantly to the Th1-like subset. Among noteworthy differences between the mouse strains was a clear deficiency of CD8 þ T cells in B6 cultures, and an unusually high proportion of CD3 þ CD4 -CD8 -(double-negative) T cells in B10.M cultures following a high-dose immunization.

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