Abstract
Combined agonist stimulation of the TNFR costimulatory receptors 4-1BB (CD137) and OX40(CD134) has been shown to generate supereffector CD8 T cells that clonally expand to greater levels, survive longer, and produce a greater quantity of cytokines compared to T cells stimulated with an agonist of either costimulatory receptor individually. In order to understand the mechanisms for this effect, we have created a mathematical model for the activation of the CD8 T cell intracellular signaling network by mono- or dual-costimulation. We show that supereffector status is generated via downstream interacting pathways that are activated upon engagement of both receptors, and in silico simulations of the model are supported by published experimental results. The model can thus be used to identify critical molecular targets of T cell dual-costimulation in the context of cancer immunotherapy.
Highlights
T cell receptors are transmembrane receptors that play a critical role in modifying the T cell response after innate immune cells have presented antigen to the T Cell Receptor (TCR)
We note that while OX40 is considered to be more active in CD4 (T helper) cells, and 4-1BB in CD8 T cells[31], OX40 activity has been found to be important for activated CD8 T cell survival, proliferation, and cytokine production[32,33], we model the action of both receptors on CD8 T cells
We have developed a stochastic multistate discrete model of CD8 T cell costimulatory receptor dual costimulation by agonists 4-1BB and OX40
Summary
T cell receptors are transmembrane receptors that play a critical role in modifying the T cell response after innate immune cells have presented antigen to the T Cell Receptor (TCR). The molecular mechanisms by which the effect of dual costimulation occurs have not been completely elucidated Both 4-1BB and OX40 costimulatory receptors belong to the Tumor Necrosis Factor Receptor (TNFR) family, and act by binding to TNF receptor-associated factor (TRAF)-acting proteins, but they bind a different subset of TRAFs16, signal through overlapping[5,16], and non-overlapping[17] pathways, and preferentially activate different subsets of lymphocytes[5]. Their dual action in generating supereffector T cells may occur at either the intracellular, network-level scale via optimized network activation, at the population-scale via activation of the major subsets of T cells, or both. The models all provided insight into dynamics of specific downstream pathways in T cell signaling, but did not include the TNFR family receptors 4-1BB or OX40 or their downstream components
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