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-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. © 2016,public library of science. all rights reserved.