Adjuvant conditioning shapes the adaptive immune response promoting immunotolerance via NLRP3/interleukin-1

Although adjuvants typically enhance immune responses, we show that repeated alum administration-termed adjuvant conditioning (AC)-induces an immunosuppressive environment that delays allogeneic graft rejection by expanding myeloid-derived suppressor cells (MDSCs). AC-induced MDSCs suppress antigen-specific adaptive responses both in vitro and in vivo, a process dependent on NLRP3 and IL-1 signaling. Allogeneic pancreatic islets transplanted into AC-treated NLRP3^-/- mice are not protected, confirming the necessity of NLRP3. Moreover, AC-induced MDSCs cultured with LPS exhibit reduced pro-inflammatory and increased immunosuppressive cytokine production. Similarly, prolonged alum exposure blunts inflammatory cytokine production in human cells. Together, these findings reveal that AC establishes an immunosuppressive milieu via the NLRP3/IL-1 axis. This work suggests that targeting this pathway could promote allograft tolerance in transplant recipients.