Innate allorecognition induces HSP70 in monocytes contributing to renal allograft rejection

After encountering allogeneic nonself, monocytes differentiate to DCs, which in turn activate the adaptive immune system that drives transplant rejection. The downstream mechanisms of allorecognition are largely unknown. We analyzed scRNA-seq data sets to identify transcriptional changes in monocytes occurring after allostimulation. Hspa1a, which encodes HSP70, was upregulated in monocytes after allostimulation in contrast to syngeneic controls in mice lacking T, B, and NK cells. Similar findings were seen in scRNA-seq data derived from kidney biopsies of rejecting transplant patients. To validate the role of HSP70 in innate allorecognition and transplantation, we performed allogeneic bone marrow plug and kidney transplantation into WT, Hspa1a/Hspa1b-/-, and DSG-treated (HSP70 inhibitor) B6 mice and examined the graft immune infiltrate. Histology, T cell infiltration, and survival were assessed in kidney transplanted mice. In both models, DSG-treated or HSP70-KO recipients displayed significantly reduced infiltration by monocyte-derived DCs (mo-DC). Chronic rejection of Balb/c kidney grafts in WT B6 recipients was attenuated in DSG-treated and HSP70-KO recipients as indicated by a reduction in Banff score. Further experiments demonstrated that in vitro allostimulated immature HSP70-KO BMDC showed less maturation compared with WT BMDC. Targeting HSP70 in innate immune cells offers a novel approach to reduce chronic kidney graft rejection.