CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease

Sakai, ShunsukeKauffman, Keith D.Sallin, Michelle A.Sharpe, ArleneYoung, Howard A.Ganusov, Vitaly V.Barber, Daniel L.2016-07-142016Sakai, Shunsuke, Keith D. Kauffman, Michelle A. Sallin, Arlene H. Sharpe, Howard A. Young, Vitaly V. Ganusov, and Daniel L. Barber. 2016. “CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease.” PLoS Pathogens 12 (5): e1005667. doi:10.1371/journal.ppat.1005667. http://dx.doi.org/10.1371/journal.ppat.1005667.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662042IFN-γ–producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ–producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-γ by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-γ production by the CXCR3+KLRG1-CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-γ in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-γ production by PD-1 to prevent lethal immune-mediated pathology.en-USBiology and Life SciencesCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsT Helper CellsImmune CellsImmunologyMedicine and Health SciencesOrganismsBacteriaActinobacteriaMycobacterium TuberculosisPhysiologyImmune PhysiologySpleenT CellsInfectious DiseasesBacterial DiseasesTuberculosisTropical DiseasesInfectious Disease ControlCytokinesImmune SystemInnate Immune SystemDevelopmental BiologyMolecular DevelopmentSpecimen Preparation and TreatmentStainingCell StainingCD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal DiseaseJournal Article2016-07-1410.1371/journal.ppat.1005667