Mathematical Modeling of T-cell Exhaustion and PD-1 Blockade in Chronic Infections
- Author(s): Jagadish, Bharath
- Advisor(s): Read, Elizabeth
- et al.
Immune responses to persistent viral infections often fail because of intense regulation of antigen-specific T-cells-a process referred to as T cell exhaustion, characterized by progressive impairment of cytokine expression, cytotoxicity, and proliferative potential. Reinvigorating exhausted T-cells is considered a promising immunotherapeutic approach to combating chronic viral infections. The inhibitory receptor programmed death 1 (PD-1), is remarkably up-regulated on the surface of exhausted virus-specific CD8+ T-cells. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1) restores CD8+ T-cell function and reduces viral load. However, the mechanisms that underlie the induction of exhaustion are not completely understood. To investigate the role of PD-1 signaling in chronic viral infections, we have developed a simple mathematical model, formulated as a system of ordinary differential equations, to dissect the dynamics of virus-infected cells, CD8+ T-cells and PD-1 signaling. We estimate rate parameter regimes by fitting to published experiments on mice chronically infected by LCMV. Blockade experiments are performed in silico by abruptly reducing PD-1 signaling during the chronic phase of infection. Our simulations replicate experimental results, showing an increase in frequency and effector function of CD8+ T-cells and decreased viral load upon PD-1 blockade. We use our mathematical model to analyze published measurements of single- and combination-blockade therapy of chronically infected mice. Our analysis shows that anti-LAG3 and anti-TIM3 modulate CD8+ T-cells activity by different mechanisms. Our analysis furthermore shows that the combination blockade by anti-TIM3 and anti-PDL1 results in a synergistic decrease of viral load, whereas the anti-LAG3/anti-PDL1 combination does not.