Liu L, Fang C, Fu W, et al. - Given an inclination to the formation of donor-specific antibodies results from ischemia-reperfusion injury (IRI), researchers report a mechanism underlying the correlative link between IRI and donor-specific antibodies by utilizing humanized models as well as patient specimens. On endothelial cells, immunoglobulin M–dependent complement activation induced by IRI was evident, that resulted in the accumulation of an NLRP3 (NOD-like receptor pyrin domain-containing protein 3) inflammasome through a Rab5-ZFYVE21-NIK axis and upregulation of ICOS-L (inducible costimulator ligand) and PD-L2 (programmed death ligand 2). A selective expansion of a T-cell population (CD4+CD45RO+PD-1^hiICOS+CCR2+CXCR5–) showing characteristics of recently described T peripheral helper cells was induced by endothelial cell–derived interleukin-18 (IL-18). Experts concluded that the mechanism underlying the promotion of donor-specific antibody formation involves IRI-induced promoted elaboration of IL-18 from endothelial cells resulting in selective expansion of alloreactive IL-18R1+ T peripheral helper cells in allograft tissues.