Infection of human macrophages and dendritic cells with mycobacterium tuberculosis induces a differential cytokine gene expression that modulates T cell response

Macrophages and dendritic cells (DQ play an essential role in the initiatio n and maintenance of immune response to pathogens. To analyze early interac tions between Mycobacterium tuberculosis (Mtb) and immune cells, human peri pheral blood monocyte-derived macrophages (MDM) and monocyte-derived dendri tic cells (MDDC) were infected with Mtb. Both cells were found to internali ze the mycobacteria, resulting in the activation of MDM and maturation of M DDC as reflected by enhanced expression of several surface Ags. After Mtb i nfection, the proinflammatory cytokines INF-alpha, IL-12 and IL-6 were secr eted mainly by MDM. As regards the production of IFN-gamma -inducing cytoki nes, IL-12 and IFN-alpha, was seen almost exclusively from infected MDDC, w hile IIL-18 was secreted preferentially by macrophages. Moreover, Mtb-infec ted MDM also produce the immunosuppressive cytokine IIL-10. Because IL-10 i s a potent inhibitor of IL-12 synthesis from activated human mononuclear ce lls, we assessed the inhibitory potential of this cytokine using soluble IL -10R. Neutralization of IL-10 restored IL-12 secretion from Mtb-infected MD M. In line with these findings, supernatants from Mtb-infected MDDC induced IFN-gamma production by T cells and enhanced IL-18R expression, whereas su pernatants from MDM failed to do that. Neutralization of IFN-alpha, IL-12, and IL-18 activity in Mtb-infected MDDC supernatants by specific Abs sugges ted that IL-12 and, to a lesser extent, IFN-alpha and IL-18 play a signific ant role in enhancing IFN-gamma synthesis by T cells. During Mtb infection, macrophages and DC may have different roles: macrophages secrete proinflam matory cytokines and induce granulomatous inflammatory response, whereas DC are primarily involved in inducing antimycobacterial T cell immune respons e.