Stimulation of dendritic cells via CD40 enhances immune responses to Mycobacterium tuberculosis infection

The resolution of pulmonary tuberculosis (TB) critically depends on the dev elopment of the Th1 type of immune responses, as exemplified by the exacerb ation of TB in IL-12-deficient mice. Therefore, vaccination strategies opti mizing IL-12 production by antigen-presenting cells (APC) in response to my cobacteria may have enhanced protective efficacy. Since dendritic cells (DC ) are the critical APC for activation of CD4(+) and CD8(+) T cells, we exam ined whether stimulation of Mycobacterium bovis bacillus Calmette Guerin (B CG)infected DC via CD40 increased their ability to generate Th1-oriented ce llular immune responses. Incubation of DC with an agonistic anti-CD40 antib ody activated CD40 signaling in DC, as shown by increased expression of maj or histocompatibility complex class II and costimulatory molecules, mRNA pr oduction for proinflammatory cytokines and interleukin 12 (IL-12) p40. This activation pattern was maintained when DC were stimulated with anti-CD40 a ntibody and infected with BCG. Importantly, CD40-stimulated BCG-infected DC displayed increased capacity to release bioactive IL-12 and to activate ga mma interferon (IFN-gamma) producing T cells in vitro. Moreover, when C57BL /6 mice were immunized,vith these DC and challenged with aerosol Mycobacter ium tuberculosis, increased levels of mRNA for IL-12 p40, IL-18, and IFN-ga mma were present in the draining mediastinal lymph nodes. However, the myco bacterial burden in the lungs was not reduced compared to that in mice immu nized with BCG-infected non-CD40 stimulated DC. Therefore, although the man ipulation of DC via CD40 is effective for enhancing immune responses to myc obacteria in vivo, additional strategies are required to increase protectio n against virulent M. tuberculosis infection.