In contrast to conventional dendritic cells (cDCs) that are constantly exposed to microbial signals at anatomical barriers, cDCs in systemic lymphoid organs are sheltered from proinflammatory stimulation in the steady state but respond to in-flammatory signals by gaining specific immune functions in a process referred to as maturation. Recent findings show that, during maturation, a population of systemic tolerogenic cDCs undergoes an acute tumor necrosis factor alpha (TNF alpha)-mediated cell death, resulting in the loss of tolerance-inducing capacity. This tolerogenic cDC population is restored upon return to the homeostatic baseline. We propose that such a dynamic reshaping of cDC populations becomes the foundation of a novel framework for maintaining tolerance at the steady state while being conducive to unhampered initiation of immune responses under pro-inflammatory conditions.
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