Modeling the Effects of Immunosuppressive PD-L1 Biomaterials on T Cell Proliferation in the Lymph Node Microenvironment

The checkpoint signaling pathway comprising programmed cell death 1 receptor (PD-1) and programmed cell death receptor ligand 1 (PD-L1) has been well characterized as a mechanism employed by cancer cells to evade T cell-mediated cell death by inducing exhaustion of T cells. The role of PD-1/PD-L1 in mediating immune evasion of cancer cells and the framework of prior work in cancer immunology presents an opportunity to develop a strategy to facilitate the treatment of autoimmune disorders arising from a loss of immune self-regulation. We hypothesized that modeling key interactions between antigen presenting cells and T cells will provide experimental parameters for PD-L1-mediated suppression of autoreactive T cells. To test the hypothesis, we developed an agent-based model to simulate T cell interactions with PD-L1-functionalized tolerogenic artificial antigen-presenting cells (TaAPCs) and dendritic cells in the lymph node paracortex. By comparing the proliferation profiles of different interaction mechanisms and at a range of TaAPC concentrations, we aimed to comprehensively map the parameters for PD-L1-mediated suppression and provide a framework for how PD-L1 expressing biomaterials might control T cell activation and proliferation. Our model quantified T cell expansion at a range of TaAPC concentrations and tested previously predicted immunosuppressive mechanisms to generate proliferation profiles for experimental validation. The computational framework developed herein is an adaptable tool for elucidating PD-1/PD-L1 interactions in the LN microenvironment and predicting suppression of T cells participating in autoimmune diseases.