Protective Immunity to Mycobacterium tuberculosis Infection by Chemokine and Cytokine Conditioned CFP-10 Differentiated Dendritic Cells

Abstract

BackgroundDendritic cells (DCs) play major roles in mediating immune responses to mycobacteria. A crucial aspect of this is the priming of T cells via chemokines and cytokines. In this study we investigated the roles of chemokines RANTES and IP-10 in regulating protective responses from Mycobacterium tuberculosis (M. tb) 10 kDa Culture Filtrate Protein-10 (CFP-10) differentiated DCs (CFP10-DCs).Methods and FindingsInfection of CFP10-DCs with mycobacteria down-modulated RANTES and IP-10 levels. Pathway specific microarray analyses showed that in addition to RANTES and IP-10, mycobacteria infected CFP10-DCs showed reduced expression of many Th1 promoting chemokines and chemokine receptors. Importantly, T cells co-cultured with RANTES and IP-10 conditioned CFP10-DCs mediated killing of mycobacteria from infected macrophages. Similarly, T cells recruited by RANTES and IP-10 conditioned CFP10-DCs mediated significant killing of mycobacteria from infected macrophages. IFN-gamma treatment of CFP10-DCs restored RANTES and IP-10 levels and T cells activated by these DCs mediated significant killing of virulent M. tb inside macrophages. Adoptive transfer of either RANTES and IP-10 or IL-12 and IFN-gamma conditioned CFP10-DCs cleared an established M. tb infection in mice. The extent of clearance was similar to that obtained with drug treatment.ConclusionsThese results indicate that chemokine and cytokine secretion by DCs differentiated by M. tb antigens such as CFP-10 play major roles in regulating protective immune responses at sites of infection.

Suppression of Dendritic Cell-mediated Responses by Genes in Calcium and Cysteine Protease Pathways during Mycobacterium tuberculosis Infection

“…As reported by others, several responses observed with live infections can be reproduced by stimulating immune cells such as DCs or macrophages with M. tuberculosis antigens (22,(42)(43)(44). To this end, we also recently reported the role of antigens expressed inside of M. tuberculosis-infected macrophages as a function of infection and time in modulating M. tuberculosis-mediated responses to DCs and macrophages (23).…”

Suppression of TLR2-Induced IL-12, Reactive Oxygen Species, and Inducible Nitric Oxide Synthase Expression byMycobacterium tuberculosisAntigens Expressed inside Macrophages during the Course of Infection

“…In addition, CFP-10 DCs modulate ROS levels, leading to increased survival of mycobacteria within DCs (25). Conditioning DCs with appropriate cytokines and chemokines results in the mounting of protective responses and the clearance of an established M. tuberculosis infection in mice (36).…”

Innate Immune Gene Polymorphisms in Tuberculosis

“…M. tuberculosis infection of human alveolar macrophages induces the production of RANTES, which reduces intracellular bacterial growth (194). The role of RANTES in protective immunity to M. tuberculosis infection has also been reported in mouse macrophages (191) and in knockout mice (252).…”