First, the authors observed that the TReg cell compartment is very dynamic in the steady state, with TReg cells proliferating more frequently than conventional T cells. Second, they used an intricate transgenic mouse system to study the response of the forkhead box P3 (FOXP3)-expressing TReg cell population to perturbations in the number of TReg cells. The Foxp3 gene is located on each of the two X chromosomes in females, one of which is stochastically inactivated in somatic cells. So, in heterozygous Foxp3–THY1.1 × Foxp3–DTR female mice, 50% of TReg cells express the congenic marker THY1.1 on their cell surface and the rest express the human diphtheria toxin receptor (DTR). Treatment of these mice with diphtheria toxin resulted in the deletion of half of the total TReg cell population, which was followed by a sixfold increase in the number of THY1.1-positive TReg cells through enhanced proliferation and survival. This homeostatic expansion of the TReg cell population depended on co-stimulatory signalling and increased interleukin-2 (IL-2) expression by conventional T cells.
The homeostatic expansion of the TReg cell population in response to partial TReg cell deletion was followed by a contraction phase, during which the excess of newly generated TReg cells was removed through the intrinsic pathway of apoptosis, which involves BCL-2 antagonist/killer (BAK), BCL-2-associated X protein (BAX) and BCL-2-interacting mediator of cell death (BIM; also known as BCL-2L11). But how is this apoptotic pathway so dynamically regulated during the expansion and the contraction phases?
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