CD4+ T Cell-Dependent IFN-γ Production by CD8+ Effector T Cells in Mycobacterium tuberculosis Infection

Both CD4(+) and CD8(+) T cells contribute to immunity to tuberculosis, and both can produce the essential effector cytokine IFN-gamma. However, the precise role and relative contribution of each cell type to in vivo IFN-gamma production are incompletely understood. To identify and quantitate the cells that produce IFN-gamma at the site of Mycobacterium tuberculosis infection in mice, we used direct intracellular cytokine staining ex vivo without restimulation. We found that CD4(+) and CD8(+) cells were predominantly responsible for production of this cytokine in vivo, and we observed a remarkable linear correlation between the fraction of CD4(+) cells and the fraction of CD8(+) cells producing IFN-gamma in the lungs. In the absence of CD4(+) cells, a reduced fraction of CD8(+) cells was actively producing IFN-gamma in vivo, suggesting that CD4(+) effector cells are continually required for optimal IFN-gamma production by CD8(+) effector cells. Accordingly, when infected mice were treated i.v. with an MHC-II-restricted M. tuberculosis epitope peptide to stimulate CD4(+) cells in vivo, we observed rapid activation of both CD4(+) and CD8(+) cells in the lungs. Indirect activation of CD8(+) cells was dependent on the presence of CD4(+) cells but independent of IFN-gamma responsiveness of the CD8(+) cells. These data provide evidence that CD4(+) cell deficiency impairs IFN-gamma production by CD8(+) effector cells and that ongoing cross-talk between distinct effector T cell types in the lungs may contribute to a protective immune response against M. tuberculosis. Conversely, defects in these interactions may contribute to susceptibility to tuberculosis and other infections. The Journal of Immunology, 2012, 189: 2530-2536.