| Popis: |
The elderly are particularly susceptible to tuberculosis due to declining immune function. Despite being more susceptible, studies have shown that old mice display an early, transient resistance to M. tuberculosis (M. tb) infection, marked by higher levels of TH1 cytokines (IL-12 and IL-18) and an expanded population of CD44hi CD8 T cells capable of producing increased levels of IFN-γ in response to TH1 cytokines, thus leading to fewer bacteria in the lungs of old mice. Herein we investigated the role of IL-12 in this early resistance phenotype in old mice by examining the source of IL-12p40 in the lungs of old mice during M. tb infection, and by comparing IL-12 responsiveness of CD8 T cells from young and old mice. We demonstrated that pulmonary CD11c+ cells were the primary source of IL-12p40 in the lungs of both young and old mice following in vitro and in vivo M. tb infection. Furthermore, we showed that in contrast to pulmonary CD11c+ cells from young mice, M. tb induced IL-12p40 production by pulmonary CD11c+ cells from old mice did not require TLR-2, and instead likely involved TLR-4 and/or TLR-9. These data indicate that pulmonary CD11c+ cells from old mice have adapted an alternative mechanism for producing IL-12p40 upon M. tb infection. In addition, we demonstrated that IL-12 responsiveness was enhanced in CD44hi CD8 T cells from old mice, as these cells had increased levels of IL-12Rβ2 gene expression and IL-12 induced STAT-4 phosphorylation compared to young CD8 T cells. Moreover, we showed that increased TH1 cytokine induced IFN-γ production by CD8 T cells from old mice correlated with increased IL-12 signaling, thus providing evidence that increased levels of IFN-γ in the lungs of old mice following M. tb infection is the result of enhanced IL-12 signaling in CD8 T cells. We therefore have a better understanding how the cells of the innate immune system are able to contribute to the early control of M. tb infection in old mice, and can begin to translate this knowledge into the development of therapies and vaccines for the elderly to help this population combat infectious diseases. |
