Interleukin-15 mediates protection against experimental tuberculosis:: A role for NKG2D-dependent effector mechanisms of CD8+ T cells

CD8(+) T cells are involved in protection against Mycobacterium tuberculosis infection and represent a promising target for new vaccine strategies. Because IL-15 is important for the homeostasis of CD8(+) T cells, we studied the immune response in IL-15-deficient mice during tuberculosis. In the absence of IL-15, CD8(+) T cells failed to efficiently accumulate in draining lymph nodes and at the site of infection. The expression of antigen-specific effector functions, such as the production of interferon-gamma and cytotoxicity, were impaired in CD8(+) T cells, but not CD4(+) T cells, from IL-15-deficient mice. This defect was associated with an increased mortality of IL-15-deficient mice during the chronic phase of infection. The lectin-like stimulatory receptor natural killer group 2D (NKG2D) was up-regulated on CD8(+) T cells only from wild-type mice, but not from IL-15-deficient mice. Mechanistically, blocking NKG2D function with an mAb inhibited M. tuberculosis-directed CD8(+) T cell responses in vitro. We conclude that in addition to regulating the expansion of CD8(+) T cells, IL-15 is also necessary for inducing effector mechanisms in CD8(+) T cells that depend on NKG2D expression. Hence, our results implicate IL-15 and NKG2D as promising targets for modulating CD8(+) T cell-mediated protection against tuberculosis.