Protection against aerosol Mycobacterium tuberculosis infection using Mycobacterium bovis Bacillus Calmette Guérin-infected dendritic cells

136

103

Dendritic cells (DC) are unique in their ability to initiate a primary immune response by the presentation of soluble Ags to T cells. Recent studies have shown that DC also phagocytose particulate Ags including the intracellular pathogen Mycobacterium tuberculosis. However, it is not known whether DC contain the growth of intracellular organisms or allow unlimited replication. To address this question, we infected human DC with a virulent strain of M. tuberculosis and monitored the intracellular growth. The bacteria grew two orders of magnitude within 7 days of culture. Among cytokines known to modulate mycobacterial growth particularly in murine macrophages (TNF-α, IFN-γ, TGF-β, IL-4), only IL-10 modulated the growth in human DC. This effect was specific for immature dendritic cells, as IL-10 did not induce growth inhibition in human macrophages. In searching for the mechanism of growth inhibition, we found that IL-10 induces the down-regulation of the DC marker CD1, while the macrophage marker CD14 was up-regulated. Functionally, IL-10-treated cells had a reduced capacity to induce an alloresponse, but phagocytic uptake of M. tuberculosis was more efficient. We also show that DC are inferior to macrophages in containing mycobacterial growth. These findings show that IL-10 converts DC into macrophage-like cells, thereby inducing the growth inhibition of an intracellular pathogen. At the site of a local immune response, such as a tuberculous granuloma, IL-10 might therefore participate in the composition of the cellular microenvironment by affecting the maturity and function of DC.

supporting

confidence: 72%

IL-10 Converts Human Dendritic Cells into Macrophage-Like Cells with Increased Antibacterial Activity Against VirulentMycobacterium tuberculosis

Förtsch

Röllinghoff

Stenger

2000

136

103

“…In contrast, macrophages are important for microbicidal function in the granuloma because they are more efficient in killing intracellular M. tuberculosis (17) and for sustaining Th1 polarity. In summary, the present study strongly positions the IL-12-secreting dendritic cell as the bridge between innate and adaptive immunities in TB, with important implications for dendritic cell-based vaccine design strategies (19,42).…”

Section: Discussionmentioning

confidence: 65%

Mycobacterium tuberculosisInduces Differential Cytokine Production from Dendritic Cells and Macrophages with Divergent Effects on Naive T Cell Polarization

Hickman

Chan

Salgame

2002

180

144

Th1-mediated cellular responses are important for protection in tuberculosis. However, the mechanisms and APC types responsible for initiating Th1 responses are not well understood. These studies show that macrophages and dendritic cells, albeit both being APC, respond differently following Mycobacterium tuberculosis infection and thereby have different consequences for the development of naive T cells. We report that M. tuberculosis-infected dendritic cells bias the polarization of OVA peptide-specific naive transgenic T cells to the Th1 phenotype, and, in contrast, in the presence of infected macrophages naive T cells do not develop a Th1 phenotype. Comparison of the cytokine profile expressed by the infected dendritic cells and macrophages revealed several differences, the most striking being that infected macrophages did not express the Th1-promoting cytokine IL-12. These studies also show that IL-10 is responsible for the failure of IL-12 production by M. tuberculosis-infected macrophages, and that the effects of IL-10 can be overcome by IFN-γ priming. We speculate that the observed difference in response of the two APC types to M. tuberculosis infection may be a reflection of their respective roles in immune initiation and granuloma regulation.

“…Additionally, infection of human DC with live bacillus Calmette-Guérin (20), M. tuberculosis (21), Listeria monocytogenes (9), Streptococcus gordonii (22), or Leishmania major (10) results in an increase in MHC and costimulatory molecule expression and enhanced T cell-stimulatory activity (20). Similar results were obtained with murine DC; these cells also demonstrated an enhanced ability to induce T cell responses in mice (23). In our studies, we found that the 19-kDa lipoprotein from M. tuberculosis, as well as synthetic lipopeptides, induced DC maturation.…”

Section: Figurementioning

confidence: 67%

Microbial Lipopeptides Stimulate Dendritic Cell Maturation Via Toll-Like Receptor 2

Hertz¹,

Kiertscher

Godowski³

et al. 2001

321

218

The ability of dendritic cells (DC) to initiate immune responses in naive T cells is dependent upon a maturation process that allows the cells to develop their potent Ag-presenting capacity. Although immature DC can be derived in vitro by treatment of peripheral blood monocytes with GM-CSF and IL-4, additional signals such as those provided by TNF-α, CD40 ligand, or LPS are required for complete maturation and maximum APC function. Because we recently found that microbial lipoproteins can activate monocytes and DC through Toll-like receptor (TLR) 2, we also investigated whether lipoproteins can drive DC maturation. Immature DC were cultured with or without lipoproteins and were monitored for expression of cell surface markers indicative of maturation. Stimulation with lipopeptides increased expression of CD83, MHC class II, CD80, CD86, CD54, and CD58, and decreased CD32 expression and endocytic activity; these lipopeptide-matured DC also displayed enhanced T cell stimulatory capacity in MLR, as measured by T cell proliferation and IFN-γ secretion. The lipid moiety of the lipopeptide was found to be essential for induction of maturation. Preincubation of maturing DC with an anti-TLR2 blocking Ab before addition of lipopeptide blocked the phenotypic and functional changes associated with DC maturation. These results demonstrate that lipopeptides can stimulate DC maturation via TLR2, providing a mechanism by which products of bacteria can participate in the initiation of an immune response.