Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model

Abstract

Mycobacterium tuberculosis is the pathogenic bacterium that causes tuberculosis (TB), one of the most lethal infectious diseases in the world. The only vaccine against TB is minimally protective, and multi-drug resistant TB necessitates new therapeutics to treat infection. Developing new therapies requires a better understanding of the complex host immune response to infection, including dissecting the processes leading to formation of granulomas, the dense cellular lesions associated with TB. In this work, we pair experimental and computational modeling studies to explore cytokine regulation in the context of TB. We use our next-generation hybrid multi-scale model of granuloma formation (GranSim) to capture molecular, cellular, and tissue scale dynamics of granuloma formation. We identify TGF-β1 as a major inhibitor of cytotoxic T-cell effector function in granulomas. Deletion of TGF-β1 from the system results in improved bacterial clearance and lesion sterilization. We also identify a novel dichotomous regulation of cytotoxic T cells and macrophages by TGF-β1 and IL-10, respectively. These findings suggest that increasing cytotoxic T-cell effector functions may increase bacterial clearance in granulomas and highlight potential new therapeutic targets for treating TB.

Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology

“…This was further supported in later studies with experimental collaborators . While studies have explored the dynamic balance for the case of TNF, IL‐10, and TGF‐β, this concept of balance likely extends beyond these cytokines to include other pro‐ and anti‐inflammatory molecules and cell types.…”

“…Figure B shows the IL‐10 and TNF gradients in a representative contained granuloma at day 50; these gradients lead to a granuloma that contains bacteria without the cost of high inflammation and bystander cellular death. Immunohistochemical analysis of necrotic NHP granulomas further supports a key role for anti‐inflammatory cytokines …”

“…Granulomas that favor anti‐inflammatory responses fail to control bacterial growth, whereas granulomas that favor pro‐inflammatory responses may sterilize a granuloma, but at the price of increased necrosis and caseum. GranSim has been used to explore the individual roles of pro‐ and anti‐inflammatory cytokines TGF‐β, TNF, and IL‐10 and then evaluate their roles in combination to provide evidence that a balanced response to these inflammatory cytokines is necessary for granuloma formation and maintenance …”

“…The dynamics of TGF‐β, another anti‐inflammatory cytokine, can also be examined at both molecular and cellular levels within GranSim . These studies present an in silico TGF‐β knockout and predict an increase in bactericidal activity of cytotoxic T cells, thereby decreasing granuloma CFU across time.…”

“…Additionally, simulations show that both anti‐inflammatory mediators TGF‐β and IL‐10 represent distinct regulatory mechanisms within granulomas as each distinctly inhibit effector T cell and macrophage functions, respectively . Altogether, the action of each cytokine represents a unique function, but granulomas that effectively contain Mtb require that cytokines perform in harmony with other cytokines in a dynamic and balanced way.…”