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

Abstract

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.

Author Summary

The development of novel tuberculosis vaccines has been hindered by the poor understanding of the mechanisms of host-protection. It has been long-held that IFN-γ is the principle effector of CD4 T cell-mediated resistance to Mtb infection, but Mtb-specific CD4 T cells produce low amounts of IFN-γ in vivo, leading to the possibility that increasing IFN-γ production by Th1 cells might enhance control of Mtb infection. However, the precise contribution of IFN-γ to CD4 T cell-dependent protection and the outcome of increasing IFN-γ production by CD4 T cells have not been evaluated. Here we show that IFN-γ accounts for only ~30% of the cumulative CD4 T cell-mediated reduction in lung bacterial loads over the first 1.5 months of infection. Moreover, we find that increasing the per capita production of IFN-γ by CD4 T cells leads to the early death of the host. Lastly, we show that suppression of CD4 T cell-derived IFN-γ by the inhibitory receptor PD-1 is essential to prevent lethal disease. Therefore, poor control Mtb infection does not result from defective production of IFN-γ, and strategies to selectively boost it are unwarranted. Furthermore, identifying the primary mechanisms of CD4 T cell-dependent control of Mtb infection should be a priority.