Interleukin 12 (IL-12) Is Crucial to the Development of Protective Immunity in Mice Intravenously Infected with Mycobacterium tuberculosis

Abstract

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-γ (IFN-γ), 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-γ. 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-γ and the activation of antigen-specific lymphocytes capable of creating a protective granuloma.

Pulmonary Mycobacterial Granuloma

“…11,12,42,52 Furthermore, the critical role of type 1 T-cell immunity, including the role of CD4 T cells and type 1 cytokines in antimycobacterial host defense, has shown to be true for pulmonary infection elicited by exposure to either BCG or M.tb. 11,12,[53][54][55][56][57] M. bovis BCG also uss similar immune evasion strategies as M.tb to dampen host immune activation mechanisms including intracellular persistence, 58 -60 inhibiting MHC molecule expression, 42,61 and inducing IL-10 production. [37][38][39]62 Despite these described similarities, we must caution that, compared with Immunosuppression of Bacterial Granuloma 1631 AJP April 2011, Vol.…”

Therapeutic effect of DNA vaccines combined with chemotherapy in a latent infection model after aerosol infection of mice with Mycobacterium tuberculosis

“…Since the importance of IL-12 in the control of mycobacterial infections has been well documented, [40][41][42][43] many attempts have been made to use IL-12 for immunotherapy against M. tuberculosis. In humans, a low dose of IL-12 cured a patient with IFN-g-refractory pulmonary M. abscessus, and successfully induced a sputum negative conversion.…”

Genetic control of susceptibility to infection with Mycobacterium tuberculosis in mice

“…49 In humans, mutations in the IL-12R cause severe immunodeficiency, associated with recurrent intracellular infections with Mycobacterium and Salmonella. 50,51 Introduction of a null allele at the IL-12 locus on a C57Bl/6J genetic background abrogates natural resistance to infection with M. tuberculosis, 52 and Leishmania major. 53 Finally, IL-6 and its receptor (IL-6R, one subunit of which maps on Chr.3) act synergistically with a number of other growth factors and cytokines to sustain normal proliferation and maturation of macrophages, T and B cells, and megakaryocytes.…”