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

Authors

• Shunsuke Sakai, National Institute of Allergy and Infectious Diseases (NIAID)
• Keith D. Kauffman, National Institute of Allergy and Infectious Diseases (NIAID)
• Michelle A. Sallin, National Institute of Allergy and Infectious Diseases (NIAID)
• Arlene H. Sharpe, Brigham and Women's Hospital
• Howard A. Young, National Cancer InstituteFollow
• Vitaly V. Ganusov, The University of Tennessee, Knoxville
• Daniel L. Barber, National Institute of Allergy and Infectious Diseases (NIAID)Follow

Date of this Version

5-1-2016

Citation

Sakai S, Kauffman KD, Sallin MA, Sharpe AH, Young HA, Ganusov VV, et al. (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 Pathog 12(5): e1005667.

doi:10.1371/journal.ppat.1005667

Comments

The work is made available under the Creative Commons CC0 public domain dedication.

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.