| First Author | Sakai S | Year | 2016 |
| Journal | PLoS Pathog | Volume | 12 |
| Issue | 5 | Pages | e1005667 |
| PubMed ID | 27244558 | Mgi Jnum | J:245926 |
| Mgi Id | MGI:5915815 | Doi | 10.1371/journal.ppat.1005667 |
| Citation | Sakai S, et al. (2016) CD4 T Cell-Derived IFN-gamma 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 |
| abstractText | 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 ~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 ~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. |
