TNF-α sculpts a maturation process invivo by pruning tolerogenic dendritic cells.

Abstract

SUMMARYIt remains unclear how the pro-immunogenic maturation of conventional dendritic cells (cDCs) abrogates their tolerogenic functions. Here, we report that the loss of tolerogenic functions depends on the rapid death of BTLAhi cDC1s, which, in the steady state, are present in systemic peripheral lymphoid organs and promote tolerance that limits subsequent immune responses. A canonical inducer of maturation, lipopolysaccharide (LPS), initiates a burst of tumor necrosis factor alpha (TNF-α) production and the resultant acute death of BTLAhi cDC1s mediated by tumor necrosis factor receptor 1. The ablation of these individual tolerogenic cDCs is amplified by TNF-α produced by neighboring cells. This loss of tolerogenic cDCs is transient, accentuating the restoration of homeostatic conditions through biological turnover of cDCs in vivo. Therefore, our results reveal that the abrogation of tolerogenic functions during an acute immunogenic maturation depends on an ablation of the tolerogenic cDC population, resulting in a dynamic remodeling of the cDC functional landscape.