Mice Lacking Bioactive IL-12 Can Generate Protective, Antigen-Specific Cellular Responses to Mycobacterial Infection Only if the IL-12 p40 Subunit Is Present

Abstract

Recent evidence suggests that absence of the IL-12p40 subunit is more detrimental to the generation of protective responses than is the absence of the p35 subunit. To determine whether this is the case in tuberculosis, both p35 and p40 knockout mice were infected with Mycobacterium tuberculosis. Mice lacking the p40 subunit were highly susceptible to increased bacterial growth, exhibited reduced production of IFN-γ, and had increased mortality. In contrast, mice lacking the p35 subunit exhibited a moderate ability to control bacterial growth, were able to generate Ag-specific IFN-γ responses, and survived infection longer. The superior Ag-specific responses of the p35 gene-disrupted mice, when compared with the p40 gene-disrupted mice, suggest that the p40 subunit may act other than as a component of IL-12. A candidate molecule capable of driving the protective responses in the p35 gene-disrupted mice is the novel cytokine IL-23. This cytokine is composed of the IL-12 p40 subunit and a p19 subunit. In support of a role for this cytokine in protective responses to M. tuberculosis, we determined that the p19 subunit is induced in the lungs of infected mice.

Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

“…Granulomas are the protective mechanism enabling containment of MTB infection and prolonging host survival [55,[58][59][60]. Lactoferrin also promoted production of IL-12p40 from splenocytes isolated from BCG/lactoferrin immunized and boosted mice, increasing immune response that supported the development of T H 1 immunity during MTB infection [61][62][63]. Finally, the increase in IL-6 production from BCG antigen-stimulated splenocytes isolated from mice immunized and boosted with BCG/ lactoferrin is puzzling, as IL-6 is typical of a T H 2 response [64], and has inhibitory functions in macrophages relative to mycobacterial antigen presentation [65,66].…”

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.…”

IL-23 Compensates for the Absence of IL-12p70 and Is Essential for the IL-17 Response during Tuberculosis but Is Dispensable for Protection and Antigen-Specific IFN-γ Responses if IL-12p70 Is Available

“…In the absence of the IL-12p40 subunit, there is a profound loss of the protective immune response to mycobacteria (6,7), which results in increased bacterial growth, reduced production of IFN-␥, decreased Ag-specific inflammation, and increased mortality (7). In contrast, mice lacking the IL-12p35 subunit are less susceptible to Mycobacterium tuberculosis (Mtb) infection.…”

“…In contrast, mice lacking the IL-12p35 subunit are less susceptible to Mycobacterium tuberculosis (Mtb) infection. Specifically, they are able to inhibit bacterial growth to a limited degree, they can generate an Ag-specific IFN-␥ T cell response and elaborate Agspecific inflammation, and they can survive longer than the p40-deficient mice (7). The fact that both the p35-and p40-deficient mice lack IL-12p70, yet the p40-deficient mice are more susceptible to disease, implicates other p40-dependent molecules as mediators of protection in tuberculosis.…”