Abstract
Recent studies show that naïve T cells bearing identical T cell receptors experience heterogeneous differentiation and clonal expansion processes. The factors controlling this outcome are not well characterized, and their contributions to immune cell dynamics are similarly poorly understood. In this study, we develop a computational model to elaborate mechanisms occurring within and between two important physiological compartments, lymph nodes and blood, to determine how immune cell dynamics are controlled. Our multi-organ (multi-compartment) model integrates cellular and tissue level events and allows us to examine the heterogeneous differentiation of individual precursor cognate naïve T cells to generate both effector and memory T lymphocytes. Using this model, we simulate a hypothetical immune response and reproduce both primary and recall responses to infection. Increased numbers of antigen-bearing dendritic cells (DCs) are predicted to raise production of both effector and memory T cells, and distinct “sweet spots” of peptide-MHC levels on those DCs exist that favor CD4+ or CD8+ T cell differentiation toward either effector or memory cell phenotypes. This has important implications for vaccine development and immunotherapy.
Highlights
Antigen-presenting cells (APCs), especially dendritic cells (DCs), process antigens and carry information from sites of infection to secondary lymphoid organs, such as lymph nodes (LNs) [1]
Through high endothelial venules (HEVs), T cells are recruited to LNs, where they are exposed to antigenic peptides presented by MHC molecules expressed on DCs – this initiates the adaptive immune response [5,6,7,8,9]
We present a hybrid computational model that uses an agent-based modeling to capture events occurring in a LN and a non-linear ordinary differential equation (ODE) model to capture events occurring in the well-mixed compartment of blood
Summary
Antigen-presenting cells (APCs), especially dendritic cells (DCs), process antigens and carry information from sites of infection to secondary lymphoid organs, such as lymph nodes (LNs) [1]. LNs are organized such that when T cells travel through they can be efficiently scanned by DCs to identify that rare cognate encounter [10,11,12]. The expanded T cell population differentiates into two classes: effector cells, which perform immediate killing and cytokine secretion functions, and memory cells, which are reserved for long-term protection [13, 14]. These cells move out of LNs via efferent lymphatics (ELs) into blood circulation [15]. We focus on cellular-mediated events shared among immune responses during the initiation of adaptive immunity and generation of immune memory
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