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The Journal of Immunology, 2004, 173: 7490-7496.
Copyright © 2004 by The American Association of Immunologists

IL-27 Signaling Compromises Control of Bacterial Growth in Mycobacteria-Infected Mice1

John E. Pearl*, Shabaana A. Khader*, Alejandra Solache*, Leigh Gilmartin*, Nico Ghilardi{dagger}, Fred deSauvage{dagger} and Andrea M. Cooper2,*

* Trudeau Institute, Inc., Saranac Lake, NY 12983; and {dagger} Genentech Inc., South San Francisco, CA 94080

Resistance to tuberculosis (TB) is dependent on the induction of Ag-specific CD4 Th1 T cells capable of expressing IFN-{gamma}. 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-{gamma}-producing phenotype by up-regulating the transcription factor T-bet and promoting expression of the IL-12R{beta}2 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-{gamma}-producing cells is unaffected by the absence of the IL-27R, there is a significant decrease in the level of mRNA for IFN-{gamma} 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-{gamma} 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-{gamma} it does reduce the ability of CD4 T cells to produce large amounts of IFN-{gamma}. Because IFN-{gamma} is detrimental to the survival of effector T cells, we hypothesize that the reduced IFN-{gamma} within the IL-27R–/– lung is responsible for the increased accumulation of lymphocytes within the mycobacterial granuloma.




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