HMGB1-mediated CIITA super-enhancers are critical for DC trained immunity in acute-to-chronic progression of allograft rejection.

Abstract

Chronic allograft rejection is mainly mediated by indirect recognition. Dendritic cells (DCs), as the major antigen-presenting cells in indirect recognition, exhibit an enhanced antigen-presenting ability in chronic rejection, but the specific mechanism is still unclear. Here, we found that pretreatment with high mobility group box-1 protein (HMGB1) in vivo can induce trained immunity in DCs. These trained DCs demonstrated an enhanced ability to present alloantigen, accelerating allograft rejection in a CTLA4-Ig-induced chronic rejection model by upregulating the expression of MHC-II and class II major histocompatibility complex transactivator (CIITA) molecules. Mechanistically, we found that HMGB1 promoted the formation of super-enhancers (SEs) of CIITA, epigenetically reprogramming DCs and promoting trained immunity. The SEs inhibitor JQ1 reduced the expression of CIITA and MHC-II in DCs, thereby delaying the occurrence of chronic rejection. Interestingly, we identified HMGB1 as a specific inducer of SE formation in a newly named SEa region of CIITA. Targeted knockout of the CIITA's SEa region inhibited HMGB1-induced trained immunity in DCs. Taken together, our data confirm that HMGB1 can induce the formation of the SEs of CIITA, promote trained immunity in DCs, and accelerate allograft rejection, thus offering a new potential target for the treatment of chronic rejection.