In humans, the type I interferon (IFN) family consists of 13 IFN‐α subtypes, IFN‐β and IFN‐o the newly discovered IFN‐like family consists of IFN‐λ1, ‐λ2 and ‐λ3. We have investigated the expression of type I and λ IFN genes following virus infections or Toll‐like receptor (TLR) triggering in monocyte‐derived DC (MDDC) and plasmacytoid DC (pDC). We found thatall IFN‐α, ‐β, ‐o and ‐λ subtypes are expressed in influenza‐virus‐infected MDDC or pDC. Conversely, differential type I IFN gene transcription was induced in MDDC and pDC stimulated by specific TLR agonists. TLR‐9 stimulation by CpG DNA induced the expression of all IFN‐α, ‐β, ‐o and ‐λ subtypes in pDC, whereas TLR‐4 stimulation by LPS, or TLR‐3 stimulation bypoly I:C, induced only IFN‐β and IFN‐λ gene expression in MDDC. The expression pattern of IFN regulatory factor (IRF)‐5 and IRF‐7 in MDDC and pDC was also determined. IRF‐5 was constitutively expressed in the two DC subsets whereas IRF‐7 was constitutive in pDC but its expression was induced along MDDC maturation. Overall, our data indicate that the coordinated expression of IFN‐λ with IFN‐β would be of crucial importance for the maturation of DC.

Macrophages and dendritic cells (DC) play an essential role in the initiation and maintenance of immune response to pathogens. To analyze early interactions between Mycobacterium tuberculosis (Mtb) and immune cells, human peripheral blood monocyte-derived macrophages (MDM) and monocyte-derived dendritic cells (MDDC) were infected with Mtb. Both cells were found to internalize the mycobacteria, resulting in the activation of MDM and maturation of MDDC as reflected by enhanced expression of several surface Ags. After Mtb infection, the proinflammatory cytokines TNF-α, IL-1, and IL-6 were secreted mainly by MDM. As regards the production of IFN-γ-inducing cytokines, IL-12 and IFN-α, was seen almost exclusively from infected MDDC, while IL-18 was secreted preferentially by macrophages. Moreover, Mtb-infected MDM also produce the immunosuppressive cytokine IL-10. Because IL-10 is a potent inhibitor of IL-12 synthesis from activated human mononuclear cells, we assessed the inhibitory potential of this cytokine using soluble IL-10R. Neutralization of IL-10 restored IL-12 secretion from Mtb-infected MDM. In line with these findings, supernatants from Mtb-infected MDDC induced IFN-γ production by T cells and enhanced IL-18R expression, whereas supernatants from MDM failed to do that. Neutralization of IFN-α, IL-12, and IL-18 activity in Mtb-infected MDDC supernatants by specific Abs suggested that IL-12 and, to a lesser extent, IFN-α and IL-18 play a significant role in enhancing IFN-γ synthesis by T cells. During Mtb infection, macrophages and DC may have different roles: macrophages secrete proinflammatory cytokines and induce granulomatous inflammatory response, whereas DC are primarily involved in inducing antimycobacterial T cell immune response.

Significance: Recent studies have established that metabolic restrains, such as glucose restriction, impair the activities of effector T cells in the tumor microenvironment. In the same context, a huge expansion of activated Treg cells in tumor tissues has been described in mice and humans, contributing to the suppression of protective antitumor immunity. Our data demonstrate that Tregs are committed to survive and proliferate in such a hostile milieu thanks to a metabolic advantage based on the combination of glycolysis and fatty acid synthesis and oxidation. This allows Tregs to prevail over conventional T cells that rely primarily on the glycolytic pathway for their metabolic demands. Awareness of the metabolic dynamics of Tregs in tumor could provide a means for cancer immunotherapy.

We have investigated the expression of interleukin-3 receptor α (IL-3Rα) chain in primary blasts from 79 patients with acute myeloid leukemia (AML), 25 patients with B-acute lymphoid leukemia (B-ALL), and 7 patients with T-acute lymphoid leukemia (T-ALL) to evaluate a linkage between the expression of this receptor chain, blast proliferative status, and disease prognosis. Although IL-3Rα chain was scarcely expressed in most patients with T-ALL, it was overexpressed in 40% and 45% of patients with B-ALL and AML, respectively, compared with the levels observed in normal CD34⁺ progenitors. The biological and clinical significance of this overexpression pattern was investigated in AML. At the biological level, elevated IL-3Rα expression was associated with peculiar properties of leukemic blasts, specifically in 3 areas. First, in all patients the blasts expressing elevated IL-3Rα levels exhibited higher cycling activity and increased resistance to apoptosis triggered by growth factor deprivation. Second, spontaneous signal transducer and activator of transcription 5 (Stat5) phosphorylation was observed in 13% of AML patients, all pertaining to the group of patients exhibiting high IL-3Rα expression. Third, following IL-3 treatment, Stat5 was activated at higher levels in blasts with elevated IL-3Rα expression. At the clinical level, a significant correlation was observed between the level of IL-3Rα expression and the number of leukemic blasts at diagnosis, and patients exhibiting elevated IL-3Rα levels had a lower complete remission rate and survival duration than those showing normal IL-3Rα levels. These findings suggest that in AML, deregulated expression of IL-3Rα may contribute to the proliferative advantage of the leukemic blasts and, hence, to a poor prognosis.

Emerging evidence points to an important role of autophagy in the immune response mediated by dendritic cells (DC) against Mycobacterium tuberculosis (Mtb). Since current vaccination based on Bacillus Calmette-Guerin (BCG) is unable to stop the tuberculosis epidemic, a deeper comprehension of the alterations induced by Mtb in DC is essential for setting new vaccine strategies. Here, we compared the capacity of virulent (H37Rv) and avirulent (H37Ra) Mtb strains as well as BCG to modulate autophagy in human primary DC. We found that Mtb H37Rv impairs autophagy at the step of autophagosome-lysosome fusion. In contrast, neither Mtb H37Ra nor BCG strains were able to hamper autophagosome maturation. Both these attenuated strains have a functional inhibition of the 6kD early secreted antigenic target ESAT-6, an effector protein of the ESAT-6 Secretion System-1(ESX-1)/type VII secretion system. Notably, the ability to inhibit autophagy was fully restored in recombinant BCG and Mtb H37Ra strains in which ESAT-6 s...