[HTML][HTML] 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 …

S Sakai, KD Kauffman, MA Sallin, AH Sharpe… - PLoS …, 2016 - journals.plos.org
S Sakai, KD Kauffman, MA Sallin, AH Sharpe, HA Young, VV Ganusov, DL Barber
PLoS pathogens, 2016journals.plos.org
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 …
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.
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