Cooper, A.M., Magram, J., Ferrante, J. & Orme, I.M. Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J. Exp. Med. 186, 39-45

Department of Microbiology, Colorado State University, Fort Collins, Colorado 80523, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/1997; 186(1):39-45. DOI: 10.1084/jem.186.1.39
Source: PubMed


Immunity to Mycobacterium tuberculosis infection is associated with the emergence of protective CD4 T cells that secrete cytokines, resulting in activation of macrophages and the recruitment of monocytes to initiate granuloma formation. The cytokine-mediating macrophage activation is interferon-gamma (IFN-gamma), which is largely dependent on interleukin-12 (IL-12) for its induction. To address the role of IL-12 in immunity to tuberculosis, IL-12 p40(-/-) mice were infected with M. tuberculosis and their capacity to control bacterial growth and other characteristics of their immune response were determined. The IL-12 p40(-/-) mice were unable to control bacterial growth and this appeared to be linked to the absence of both innate and acquired sources of IFN-gamma. T cell activation as measured by delayed type hypersensitivity and lymphocyte accumulation at the site of infection were both markedly reduced in the IL-12 p40(-/-) mice. Therefore, IL-12 is essential to the generation of a protective immune response to M. tuberculosis, with its main functions being the induction of the expression of IFN-gamma and the activation of antigen-specific lymphocytes capable of creating a protective granuloma.

Download full-text


Available from: Andrea M Cooper,
22 Reads
    • "Moreover, mice deficient in the Th1-polarizing cytokine IL-12 (Cooper et al. 1997) or, albeit to a lesser extent, the Th1 lineage-specifying transcription factor Tbet (Sullivan et al. 2005) succumb early following Mtb exposure. Therefore, CD4 T cells polarized toward the Th1 phenotype are likely critical for host resistance to Mtb infection, and there is evidence in humans that the IL-12/IFN-g axis is also critical for control of Mtb infection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the coordinated efforts of innate and adaptive immune cells. Diverse pulmonary myeloid cell populations respond to Mtb with unique contributions to both host-protective and potentially detrimental inflammation. Although multiple cell types of the adaptive immune system respond to Mtb infection, CD4 T cells are the principal antigen-specific cells responsible for containment of Mtb infection, but they can also be major contributors to disease during Mtb infection in several different settings. Here, we will discuss the role of different myeloid populations as well as the dual nature of CD4 T cells in Mtb infection with a primary focus on data generated using in vivo cellular immunological studies in experimental animal models and in humans when available. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor Perspectives in Medicine 07/2015; DOI:10.1101/cshperspect.a018424 · 9.47 Impact Factor
  • Source
    • "IL-12, known to stimulate the growth of NK cells and T-cells, enhances the production of cytokines, and connects innate and adaptive immune responses against mycobacterial infections (Trinchieri, 1995). IL-12 has been reported to exert its protective effects in M. tuberculosis-infected mice, mainly through IFN-γ (Cooper et al., 1997). Therapeutic effect of transgenic tomato over-expressing IL-12 has been reported in a murine model of progressive pulmonary TB (Elías-López et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human tuberculosis (TB), a chronic inflammatory disease is caused by Mycobacterium tuberculosis, a facultative intramacrophage pathogen. The highly complex interactions between mycobacteria and macrophages (MΦs), characterized in part by the induction and elaboration of several cytokines including IL-1, IL-6, IL-10, IL-12 p40 and IL-12 p70 are not yet fully understood. The cytokines are known to have important bearing on the pathogenesis and host defense during TB. We thus studied different patterns of cytokines elaborated by mouse peritoneal macrophages (PMs) following their interaction with live and heat-killed, virulent and avirulent, and pathogenic and non-pathogenic mycobacteria, in vitro. Pathogenic M. tuberculosis H37Rv (virulent) and M. tuberculosis H37Ra (avirulent), and non-pathogenic M. smegmatis were grown in complete Middle Brook 7H9 broth. For some experiments, mycobacteria were heat-killed (80°C; 20 min). The supernatants of cultured PMs, having ingested mycobacteria for 6 h, 24 h, 4 days and 7 days, were harvested for the quantification of IL-1, IL-6, IL-10, IL-12 p40 and IL-12 p70 by using a multiplex suspension cytokine array system. The PMs infected with heat-killed mycobacteria, as compared to their respective live counterparts, invariably elaborated significantly (p < 0.001) increased (approximately 2-3-fold) amounts of IL-6, at all the time-points studied, in vitro. Further, PMs infected with M. tuberculosis H37Ra, as compared to M. tuberculosis H37Rv, elaborated 4-5-fold more (p < 0.001) IL-6. Non-pathogenic M. smegmatis, as compared to pathogenic M. tuberculosis H37Ra and M. tuberculosis H37Rv, following infection, induced the PMs to elaborate highest (p < 0.001) amounts of IL-6 at all the time-points studied. Curiously, none of these mycobacteria-infected PMs elaborated IL-1, IL-10, IL-12 p40 and IL-12 p70, significantly. IL-6 appears to be the only major cytokine elaborated by mycobacteria-infected PMs, in vitro, and thus may function as a potent biomarker of mycobacterial infection, either stand-alone or along with other cytokines.
    SpringerPlus 12/2013; 2(1):686. DOI:10.1186/2193-1801-2-686
  • Source
    • "These patients lacking effective IL-12 and IL-12 receptor show a reduced capacity of IFNγ production. In fact, IL-12 exerts its protective roles against mycobacterial infection mainly through induction of IFNγ, thus serving as a link between innate and adaptive host immune responses [132]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tuberculosis, an infectious disease caused by Mycobacterium tuberculosis (Mtb), remains a major cause of human death worldwide. Innate immunity provides host defense against Mtb. Phagocytosis, characterized by recognition of Mtb by macrophages and dendritic cells (DCs), is the first step of the innate immune defense mechanism. The recognition of Mtb is mediated by pattern recognition receptors (PRRs), expressed on innate immune cells, including toll-like receptors (TLRs), complement receptors, nucleotide oligomerization domain like receptors, dendritic cell-specific intercellular adhesion molecule grabbing nonintegrin (DC-SIGN), mannose receptors, CD14 receptors, scavenger receptors, and FCγ receptors. Interaction of mycobacterial ligands with PRRs leads macrophages and DCs to secrete selected cytokines, which in turn induce interferon-γ- (IFNγ-) dominated immunity. IFNγ and other cytokines like tumor necrosis factor-α (TNFα) regulate mycobacterial growth, granuloma formation, and initiation of the adaptive immune response to Mtb and finally provide protection to the host. However, Mtb can evade destruction by antimicrobial defense mechanisms of the innate immune system as some components of the system may promote survival of the bacteria in these cells and facilitate pathogenesis. Thus, although innate immunity components generally play a protective role against Mtb, they may also facilitate Mtb survival. The involvement of selected PRRs and cytokines on these seemingly contradictory roles is discussed.
    11/2013; 2013(5):179174. DOI:10.1155/2013/179174
Show more