Infection of Human Macrophages and Dendritic Cells withMycobacterium tuberculosisInduces a Differential Cytokine Gene Expression That Modulates T Cell Response

Abstract

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.

Mycobacterium tuberculosisAntigens Specifically Modulate CCR2 and MCP-1/CCL2 on Lymphoid Cells from Human Pulmonary Hilar Lymph Nodes

“…Mtb Ag did not affect expression of costimulatory molecules by any of the cell populations studied. These results contrast with previous reports that show up-regulation of these molecules by Mtb on monocyte-derived DC (28,31) and monocyte-derived macrophages (31). Discrepancy between these results may be due to the different origin of the cells, i.e., blood monocyte-derived macrophages/DC vs PHLN, or simply that APC from PHLN respond differently to Mtb than blood-derived cells.…”

“…It is here where DC have intimate interaction with Mtb Ag-specific naive T cells, thus facilitating Ag presentation, T cell activation and proliferation, and, through production of the appropriate cytokines, their subsequent differentiation toward Th1 type effector cells (29,30). Although both macrophages and DC are able to phagocytose/endocytose Mtb, up-regulation of costimulatory molecules and Ag presentation capacity are more remarkable in DC (28,29,31).…”

Recombinant MPT83 Derived fromMycobacterium tuberculosisInduces Cytokine Production and Upregulates the Function of Mouse Macrophages through TLR2

“…TNF-a is important for granuloma formation and the induction of cytotoxicity against M. tuberculosis bacilli (55,56). In contrast, IL-12 plays a crucial role in activating the protective Th1 immune response (57)(58)(59). Interestingly, the virulence of pathogenic mycobacteria is correlated inversely with the levels of IL-12 and TNF-a (60-63).…”

Mycobacterium bovis and BCG induce different patterns of cytokine and chemokine production in dendritic cells and differentiation patterns in CD4+ T cells

“…As the genome sequences of M.tb and M. bovis show over 99.95 % identity, and the pathological changes caused by M. bovis in cattle are also similar to those of human TB, M. bovis and its isogenic attenuated strain BCG are ideal model strains for studying M.tb pathogenesis and immunity. also contribute to the cellular immune response against mycobacterium infection (Giacomini et al, 2001;Tascon et al, 2000;Sanarico et al, 2011). However, unlike macrophages, the involvement of DCs in M.tb infection is poorly defined.…”