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.

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

“…Thus, solely stimulating Th1 immunity might not be the solution in TB prevention. This is confirmed in a mouse TB study showing that increasing IFN-γ production by T-cells in the lungs is detrimental to the host due to hyper-inflammation that requires PD-1-mediated suppression to limit pathology (33). In line with this, Mtb-infected mice deficient in PD-1, or mice in which PD-1 is selectively inhibited, display excessive inflammation and disease progression (34, 35).…”

“…In TB circulating PMN primarily express the T1-IFN signature but also overexpress PD-L1 (58, 347). The interaction of PD-L1 with PD1 on CD4 + T-cells is a key immunological checkpoint in TB that limits excessive T-helper responses (33, 35). In line with this, PD1-deficient mice are extraordinarily susceptible to TB (34).…”

“The Impact of Mycobacterium tuberculosis Immune Evasion on Protective Immunity: Implications for TB Vaccine Design” – Meeting report

“…Thus, CD4+ T cell-derived IFNγ can be protective in one tissue, while simultaneously being detrimental in another. He noted that the presence of cytokine receptors in the local environment also needs to be considered [51]. …”

Development of an interferon-γ release assay (IGRA) for detection of Brucella abortus and clinical diagnosis of brucellosis

“…Similarly, Mycobacterium bovis is an intracellular bacterial pathogen inducing high levels of IFN-γ in PB cells when animals are stimulated by tuberculin [9]. Therefore, the secretion of IFN-γ is an indicator for Mycobacterium infection, and was used to establish an IGRA, which was subsequently applied clinically for the detection of bovine tuberculosis [10].…”