One approach to study the role of distinct cellular mechanisms in susceptibility/resistance to tuberculosis (TB) is to compare parameters of response to infection in the lungs of mouse strains exhibiting genetically determined differences in TB susceptibility/severity. Interstrain differences in antimycobacterial macrophage reactions, T cell responses & inflammation in the lungs of TB-susceptible I/St, TB-resistant A/Sn and (I/St x A/Sn)F1 mice were analysed following intratracheal inoculation of 103 CFUs of M. tuberculosis H37Rv. The antimycobacterial responses in the lungs of susceptible I/St mice were characterized by: (i) increased inflammatory infiltration by all major immune cell subsets; (ii) decreased type 1 cytokine production; (iii) impaired antimycobacterial activity of lung macrophages; (iv) unusually high proliferation of lung T lymphocytes. Differences in several parameters of anti-TB immunity between susceptible and resistant mice corresponded well to the polygenic pattern of TB control previously established in this mouse model. Importantly, lung macrophages isolated from noninfected mice were unable to respond to IFN-gamma by increasing their mycobactericidal function, but between weeks 3 and 5 of the infection this capacity developed in all mice. However, by this time point susceptible but not resistant mice demonstrated a pronounced decrease in IFN-gamma production by lung cells. This chain of events may explain the inability of I/St mice to control both early and chronic TB infection.