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IL-27 Signaling Compromises Control of Bacterial Growth in Mycobacteria-Infected Mice

2004; American Association of Immunologists; Volume: 173; Issue: 12 Linguagem: Inglês

10.4049/jimmunol.173.12.7490

1550-6606

John E. Pearl, Shabaana A. Khader, Alejandra Solache, Leigh Gilmartin, Nico Ghilardi, Fred deSauvage, Andrea M. Cooper,

Cytokine Signaling Pathways and Interactions

Abstract Resistance to tuberculosis (TB) is dependent on the induction of Ag-specific CD4 Th1 T cells capable of expressing IFN-γ. Generation of these T cells is dependent upon IL-12p70, yet other cytokines have also been implicated in this process. One such cytokine, IL-27, augments differentiation of naive T cells toward an IFN-γ-producing phenotype by up-regulating the transcription factor T-bet and promoting expression of the IL-12Rβ2 chain allowing T cells to respond to IL-12p70. We show that the components of IL-27 are induced during TB and that the absence of IL-27 signaling results in an altered disease profile. In the absence of the IL-27R, there is reduced bacterial burden and an increased lymphocytic character to the TB granuloma. Although the number of Ag-specific CD4 IFN-γ-producing cells is unaffected by the absence of the IL-27R, there is a significant decrease in the level of mRNA for IFN-γ and T-bet within the lungs of infected IL-27R−/− mice. Ag-specific CD4 T cells in the lungs of IL-27R−/− also produce less IFN-γ protein per cell. The data show that expression of IL-27 during TB is detrimental to the control of bacteria and that although it does not affect the number of cells capable of producing IFN-γ it does reduce the ability of CD4 T cells to produce large amounts of IFN-γ. Because IFN-γ is detrimental to the survival of effector T cells, we hypothesize that the reduced IFN-γ within the IL-27R−/− lung is responsible for the increased accumulation of lymphocytes within the mycobacterial granuloma.