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

Abstract

IL-12p70 induced IFN-γ is required to control Mycobacterium tuberculosis growth; however, in the absence of IL-12p70, an IL-12p40-dependent pathway mediates induction of IFN-γ and initial bacteriostatic activity. IL-23 is an IL-12p40-dependent cytokine containing an IL-12p40 subunit covalently bound to a p19 subunit that is implicated in the induction of CD4 T cells associated with autoimmunity and inflammation. We show that in IL-23 p19-deficient mice, mycobacterial growth is controlled, and there is no diminution in either the number of IFN-γ-producing Ag-specific CD4 T cells or local IFN-γ mRNA expression. Conversely, there is an almost total loss of both IL-17-producing Ag-specific CD4 T cells and local production of IL-17 mRNA in these mice. The absence of IL-17 does not alter expression of the antimycobacterial genes, NO synthase 2 and LRG-47, and the absence of IL-23 or IL-17, both of which are implicated in mediating inflammation, fails to substantially affect the granulomatous response to M. tuberculosis infection of the lung. Despite this redundancy, IL-23 is required to provide a moderate level of protection in the absence of IL-12p70, and this protection correlates with a requirement for IL-23 in the IL-12p70-independent induction of Ag-specific, IFN-γ-producing CD4 T cells. We also show that IL-23 is required for the induction of an IL-17-producing Ag-specific phenotype in naive CD4 T cells in vitro and that absence of IL-12p70 promotes an increase in the number of IL-17-producing Ag-specific CD4 T cells both in vitro and in vivo.

Increased circulating interleukin (IL)-23 in children with malarial anemia: In vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10

“…Additional studies in samples collected prospectively in malarial-infected children at different time points throughout the course of infection are required to more definitively examine the inter-relationships among IL-23, IL-12, and IL-10 in vivo. Since IL-23 and IL-12 have distinct roles in the induction of immunity to intracellular pathogens [21,[52][53][54], as well as different downstream signaling pathways [55], it is important that these pathways be further investigated to delineate the role of IL-23 and IL-12 in malarial anemia pathogenesis. As such, we are currently investigating the role of the IL-23 and IL-12 pathways in prospectively collected samples from children naturally exposed to P. falciparum.…”

Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

“…IL-23 KO mice control M. tuberculosis at the same level as WT mice (40). IL-23 enhances the induction of IL-17A-producing Ag-specific CD4 + T cells (40,41) and induces IL-17A production by TCR gd T cells (42).…”

CD4 T cells producing pro-inflammatory interleukin-17 mediate high pathology in schistosomiasis

“…The origin of IL-23 and other possible activating signals is ascribed to innate immunocytes, although the precise pathogen-derived stimuli are not known. Th IL-17 cells have been shown to participate in an increasing number of host responses stimulated by a variety of self antigens and pathogens (Infante-Duarte et al 2000, Lubberts et al 2004, Happel et al 2005, Khader et al 2005, Langrish et al 2005, Kleinschek et al 2006, Mensah-Brown et al 2006. It now is of great interest and importance to ascertain their presence and activity in human diseases including schistosomiasis.…”