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 …

SA Khader, JE Pearl, K Sakamoto… - The Journal of …, 2005 - journals.aai.org
SA Khader, JE Pearl, K Sakamoto, L Gilmartin, GK Bell, DM Jelley-Gibbs, N Ghilardi
The Journal of Immunology, 2005journals.aai.org
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 …
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.
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