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

IFN-gamma-producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-gamma contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-gamma production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-gamma accounts for only similar to 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-gamma-producing capacity of CD4 T cells by similar to 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-gamma by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-gamma 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-gamma in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-gamma production by PD-1 to prevent lethal immune-mediated pathology.