Interleukin-23 Restores Immunity to Mycobacterium tuberculosis Infection in IL-12p40-Deficient Mice and Is Not Required for the Development of IL-17-Secreting T Cell Responses

Abstract

Host control of Mycobacterium tuberculosis is dependent on the activation of CD4+ T cells secreting IFN-γ and their recruitment to the site of infection. The development of more efficient vaccines against tuberculosis requires detailed understanding of the induction and maintenance of T cell immunity. Cytokines important for the development of cell-mediated immunity include IL-12 and IL-23, which share the p40 subunit and the IL-12Rβ1 signaling chain. To explore the differential effect of IL-12 and IL-23 during M. tuberculosis infection, we used plasmids expressing IL-23 (p2AIL-23) or IL-12 (p2AIL-12) alone in dendritic cells or macrophages from IL-12p40−/− mice. In the absence of the IL-12/IL-23 axis, immunization with a DNA vaccine expressing the M. tuberculosis Ag85B induced a limited Ag-specific T cell response and no control of M. tuberculosis infection. Codelivery of p2AIL-23 or p2AIL-12 with DNA85B induced strong proliferative and IFN-γ-secreting T cell responses equivalent to those observed in wild-type mice immunized with DNA85B. This response resulted in partial protection against aerosol M. tuberculosis; however, the protective effect was less than in wild-type mice owing to the requirement for IL-12 or IL-23 for the optimal expansion of IFN-γ-secreting T cells. Interestingly, bacillus Calmette-Guérin immune T cells generated in the absence of IL-12 or IL-23 were deficient in IFN-γ production, but exhibited a robust IL-17 secretion associated with a degree of protection against pulmonary infection. Therefore, exogenous IL-23 can complement IL-12 deficiency for the initial expansion of Ag-specific T cells and is not essential for the development of potentially protective IL-17-secreting T cells.

T-Cell mRNA Expression in Response toMycobacterium bovisBCG Vaccination andMycobacterium bovisInfection of White-Tailed Deer

“…These data are consistent with previous reports that vaccination of mice produces similar numbers of IFN-␥-and IL-17-producing cells in the lungs (12). In addition, it has been reported that IL-17 was not required for the primary response to vaccination; however, it was required for the recall response when the mice were infected with virulent M. tuberculosis (12,48). The contribution of IL-17 to pathology is not clear; however, the absence of IL-23 and IL-17 in mice results in increased lung inflammation (14) after TB infection.…”

IL-12-Impaired and IL-12-Secreting Dendritic Cells Produce IL-23 upon CD154 Restimulation

“…Notably, murine IL-23 can drive the induction of IFN-␥-producing CD4 ϩ T cells in vivo (74). Likewise, IL-12p40 knock-out mice immunized with DNA/IL-23 plasmids, which induced the production of IL-23 but not of IL-12p70 in transfected IL-12p40 knock-out DCs, developed strong Th1 immune responses, rendering the mice partially protected against M. tuberculosis infection (75). Moreover, infection of human DCs with Bordetella pertussis inhibits IL-12p35 production through cAMP induction.…”

NKG2D-Dependent IL-17 Production by Human T Cells in Response to an Intracellular Pathogen

“…In animal models, IL-23 is essential for IL-17 production during infection by Helicobacter pylori, Pneumocystis carinii, and K. pneumoniae (18,30,31). However, for mycobacterial infection, one study showed that IL-23 was required for the IL-17 response to tuberculosis (26), but another demonstrated that IL-23 was dispensable for IL-17 production during infection with M. bovis bacillus Calmette-Guerin (32). We found that IL-23, but not IL-6 or TGF-␤, is required for T cells from persons with M. tuberculosis infection to produce IL-17 in response to mycobacterial Ags.…”