T-HELPER 1-LIKE SUBSET-SELECTION IN MYCOBACTERIUM-BOVIS BACILLUS CALMETTE-GUERIN-INFECTED RESISTANT AND SUSCEPTIBLE MICE

The Bcg gene has been shown to control natural resistance of mice to i ntravenous infection with low doses of Mycobacterium bovis (bacillus C almette-Guerin; BCG). In the present study, we evaluated the impact of the Bcg gene on the development of T-cell reactivity during the early stages of infection. Congenic strains of mice, bearing 'r' and 's' al leles of the Beg gene on B10.A and BALB/c backgrounds, were studied at different time-points for 2 weeks after infection. The in vitro proli ferative response of spleen cells, induced by mycobacteria or concanav alin A, was depressed in the Bcg(s) mice compared to the Beg(r) congen ic mice 14 days after infection with 10(5) colony-forming units (CFU) of BCG. Polymerase chain reaction (PCR)-based methodology was used to compare the level of lymphokine gene expression in the spleens of infe cted congenic mice both ex vivo and after in vitro stimulation. In bot h cases, preferential expression of interferon-gamma (IFN-gamma), lymp hotoxin, interleukin-2 (IL-2) and IL-2 receptor genes was observed. Th e lymphokine gene expression profiles indicated that T lymphocytes act ivated in the course of the BCG infection preferentially expressed the T-helper 1-specific pattern, irrespective of the allele of the Beg ge ne. We showed that this bias in T-cell differentiation could not be at tributed to either down-regulation of IL-4 gene expression or modulati on of the macrophage co-stimulatory activity by live M. bovis BCG. We conclude that the mechanism of phenotypic expression of the Bcg gene r esides in the differential ability of macrophages to be activated by l ymphokines produced by protective T cells, rather than in the lack of these lymphokines in susceptible animals.