Figure 3.

Immune tolerance cascade induced by elevated LILRB4 expression on antigen-presenting cells. LILRB4 precursor RNA is retained in the nucleus of dendritic cells, and treatment of LILRB4 precursor mRNA is triggered when dendritic cells are exposed to IL-10, IFN-α, VD3 and Ts cells. The production of mature LILRB4 transcripts after treatment is accompanied by an elevated expression of LILRB4 protein. LILRB4, through tyrosine phosphorylation of its intracellular ITIM motifs, signals for the recruitment of SHP-1/SHP-2, leading to lower phosphorylation levels of TAK1/NF-κB/MAPK and further reducing RANKL-induced signaling. Moreover, high expression of LILRB4 inhibits the transcription of intracellular co-stimulatory molecules, inflammatory cytokines, and inflammatory exosomal microRNAs. Under the multiple effects of LILRB4, dendritic cells become tolerogenic, induce the differentiation of Treg and Ts cells and inactivate CD4⁺Th cells and CD8⁺CTL cells. The differentiated Treg and Ts cells can in turn direct the differentiation of immature DCs to tolerogenic DCs by inducing the expression of the inhibitory receptor LILRB4, thus forming a complete immune tolerance cascade (illustrated using www.figdraw.com, accessed on 25 January 2024).