Abstract
Adaptive immune responses depend on interactions between T cell receptors (TCRs) and peptide major histocompatibility complex (pMHC) ligands located on the surface of T cells and antigen presenting cells (APCs), respectively. As TCRs and pMHCs are often only present at low copy numbers their interactions are inherently stochastic, yet the role of stochastic fluctuations on T cell function is unclear. Here, we introduce a minimal stochastic model of T cell activation that accounts for serial TCR-pMHC engagement, reversible TCR conformational change and TCR aggregation. Analysis of this model indicates that it is not the strength of binding between the T cell and the APC cell per se that elicits an immune response, but rather the information imparted to the T cell from the encounter, as assessed by the entropy rate of the TCR-pMHC binding dynamics. This view provides an information-theoretic interpretation of T cell activation that explains a range of experimental observations. Based on this analysis, we propose that effective T cell therapeutics may be enhanced by optimizing the inherent stochasticity of TCR-pMHC binding dynamics.
Highlights
Lymphocytes are responsible for immunity and a subset known as T cells are critical for adaptive immunity [1]
T cell receptors (TCRs) located on the T cell surface reversibly bind to peptide major histocompatibility complex ligands located on the surface of antigen presenting cells (APCs) [2]
We will introduce some information-theoretic notions in the context of a simple model of TCR-pMHC binding, before discussing how they apply to a more realistic model of T cell activation
Summary
Lymphocytes are responsible for immunity and a subset known as T cells are critical for adaptive immunity [1]. T cell receptors (TCRs) located on the T cell surface reversibly bind to peptide major histocompatibility complex ( pMHC) ligands located on the surface of antigen presenting cells (APCs) [2]. This interaction can generate a signalling cascade within the T cell [3], leading to a variety of functional responses [4], including the production of soluble messengers called cytokines [5]. An activated T cell is stimulated to proliferate, thereby generating progeny that can differentiate into effector cells [3] These mature T cells are able to clear antigen from the body by seeking out and destroying harmful pathogen-infected or tumour cells [6]. Despite decades of research, it is still unclear which TCR proximal mechanisms are primarily responsible for transmitting the information encoded in the pMHC ligand to the T cell intracellular signalling pathways [7–14]
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