@article {1051016,
	title = {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},
	journal = {PLoS Pathog},
	volume = {12},
	number = {5},
	year = {2016},
	month = {2016 May},
	pages = {e1005667},
	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.},
	issn = {1553-7374},
	doi = {10.1371/journal.ppat.1005667},
	author = {Sakai, Shunsuke and Kauffman, Keith D and Sallin, Michelle A and Sharpe, Arlene H and Young, Howard A and Ganusov, Vitaly V and Barber, Daniel L}
}
