The Duration of T Cell Stimulation Is a Critical Determinant of Cell Fate and Plasticity

Abstract

T cell receptor (TCR) signal strength determines the differentiation outcome of naïve CD4+ T cells: low signal strength favors Foxp3pos regulatory T cells (Treg) whereas high TCR signals are required to induce IL-2-producing helper T cells (Th). To better understand the signaling requirements for this cell-fate decision, we constructed a logic circuit model of the TCR signaling pathways. A major feature of this model is an incoherent feed-forward loop involving activation of Foxp3 and its inhibition by mTOR, which leads to transient appearance of Foxp3pos cells under simulation conditions that drive IL-2 producing Th cells. This behavior along with the predicted ability of TGF-β to induce Treg despite continued activation of the Akt/mTOR pathway were confirmed experimentally. The latter provides a possible reason for the observed instability of TGF-β-induced Treg. The model also predicted and experiments confirmed that transient high dose Ag stimulation results in three stable T cell fates (Th, Treg, and non-activated) with relative proportions depending on the duration of stimulation. Experimental analysis of the cell population at the time of Ag removal identified three distinct populations based on CD25 abundance and Akt/mTOR activation that correlated with these T cell fates. Further analysis of corresponding simulation trajectories implicated a negative feedback loop involving Foxp3, PTEN, and Akt/mTOR. Taken together, these results suggest that there is a critical period following TCR stimulation during which heterogeneity in the differentiating population leads to increased plasticity of cell fate.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…88). Indeed, deciphering how numerous extracellular inputs are integrated within the cell to drive the plasticity of cells towards distinct functions is daunting, but mathematical modelling has successfully recapitulated the experimental observations described here and may provide an important platform to clarify this complexity 91 .…”

Methods to Expand Cell Signaling Models Using Automated Reading and Model Checking

“…While simulations of logical models are known to be able to recapitulate certain experimental observations [3], verifying the results of the simulation against the properties manually is tedious and error-prone, especially when the number of models or properties becomes large. A feasible way to tackle this problem is to use formal methods.…”

The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study

“…The over-activation of the Akt/mTOR pathway by hyperinsulinemia plays a key role in this shift [15]. This pathway has been reported to be critical for cell fate determination in response to the TCR signalling [21]. It is highly probable that CD4+ T cell differentiation relies in redundant modules that together contribute to the dynamical robustness of the system [9,56].…”

“…Naive CD4+ T cells (Th0) are activated when they recognize an antigen in a secondary lymphoid organ. CD4+ T cells may attain different cell fates depending on the cytokine milieu, TCR stimulation, and other signals in their microenvironment [20,21]. The cytokines can be produced by the lymphocyte (intrinsic) or by other immune cells (extrinsic).…”