DCs play a key role in antigen presentation, which Entinostat results in activation of T cell populations that can lead to efficient phagocyte killing of the intracellular bacillus, via granulysin-induced phagocyte death, or by cytokine release (e.g. IFN-γ) that supports the mycobactericidal capacity of phagocytes [38–41]. Although outside the scope of this current article, it is possible that dying DCs share some properties of dying macrophages, and contribute to this T cell response. In the present study we found that both the attenuated H37Ra and virulent H37Rv strains cause death of human DCs. The caspase-independent cell death we report in H37Ra-infected DCs appears to be neither apoptosis

nor pyroptosis (both of which require caspase activity) [22, 42]. There are various modes of

non-apoptotic cell death, such as pyronecrosis and necroptosis, which can occur without caspase activation. The way in which cells die shapes the response of the immune system; death can be immunogenic, tolerogenic or silent [43, 44]. Therefore, the type of cell death undergone by Mtb-infected DCs is of interest, as it may either support or inhibit cytotoxic and helper T cell responses. Macrophage apoptosis appears to be Selleck PFT�� beneficial for the host response to tuberculosis by having direct bactericidal effects on intracellular mycobacteria and also in the stimulation of protective immunity. The genome of M. tuberculosis contains genes that actively inhibit macrophage apoptosis and enhance buy Savolitinib its intracellular survival, including nuoG, pknE and secA2 [45]. It is likely that the products of these genes would also inhibit apoptosis of DCs, possibly steering the cells towards the non-apoptotic mode of cell death seen in the present study. Interestingly, foamy macrophages (which are positive for DC markers) in granulomas Celecoxib in the lungs of mice infected with M. tuberculosis have been found to express high levels of TNFR-associated factors (TRAFs) 1-3 which are associated with resistance to apoptosis [46]. Although H37Ra and H37Rv are highly related, being derived from the same parental H37 strain, they differ in important respects at the

genetic [47], transcriptional [48] and post transcriptional [49] levels. As a result H37Ra displays several characteristics that are different from H37Rv (e.g. variations in PE/PPE/PE-PGRS proteins [47], decreased survival inside human macrophages [50, 51], differences in the composition of mannose caps on lipoarabinomannin [52] and impaired ability to secrete ESAT 6 [49]) each of which could have an impact on the mode of cell death [53, 54]. Indeed, similar to our previous finding in human macrophages [10], H37Rv infection killed DCs at a significantly faster rate than H37Ra. Further work will be needed to determine whether infection of DCs with H37Rv causes a similar caspase-independent mode of cell death. Caspases can have variable effects on the immunogenic potential of dying cells.