Gamma interferon-producing CD4(+) T lymphocytes in the lung correlate withresistance to infection with Mycobacterium tuberculosis

The human immune system efficiently limits the replication of Mycobacterium tuberculosis in most infected individuals. Only 5 to 10% of infected peopl e develop clinical tuberculosis, a sign of the inability of the immune syst em to control the infection. We have studied the C3H/HeJ (C3H) and C57BL/6 (B6) inbred mouse strains, which differ in their susceptibility to tubercul osis, in order to ascertain the immunological determinants of a successful immune response against M. tuberculosis and to establish a system to identi fy genes that influence susceptibility to tuberculosis. We found that the r esistant B6 mice were able to control infection in both the lung and spleen , while susceptible C3H mice were incapable of limiting bacteria growth, es pecially in the lung, and succumbed to infection within 4 weeks. We determi ned that the susceptibility of C3H mice was independent of the Toll-like re ceptor 4 (tlr4) genetic locus and allelic major histocompatibility complex differences. Although the splenic immune responses were similar in the two mouse strains, the local immune responses in the lungs of the infected mice differed greatly. The pulmonary immune response in resistant B6 mice was c haracterized by an early influx of both CD4(+) and CD8(+) lymphocytes that produced gamma interferon (IFN-gamma), In contrast, the immune response of C3H mice in the lung was characterized by a delayed and decreased influx of lymphocytes, which produced little IFN-gamma. These results suggest an imp ortant role for the early appearance of IFN-gamma -producing lymphocytes in the lung in resistance to infection with M. tuberculosis.