| First Author | Andrade MS | Year | 2022 |
| Journal | JCI Insight | Volume | 7 |
| Issue | 11 | PubMed ID | 35674134 |
| Mgi Jnum | J:326778 | Mgi Id | MGI:7294917 |
| Doi | 10.1172/jci.insight.159205 | Citation | Andrade MS, et al. (2022) Linked sensitization by memory CD4+ T cells prevents costimulation blockade-induced transplantation tolerance. JCI Insight 7(11):e159205 |
| abstractText | Dominant infectious tolerance explains how brief tolerance-inducing therapies result in lifelong tolerance to donor antigens and "linked" third-party antigens, while recipient sensitization and ensuing immunological memory prevent the successful induction of transplant tolerance. In this study, we juxtapose these 2 concepts to test whether mechanisms of dominant infectious tolerance can control a limited repertoire of memory T and B cells. We show that sensitization to a single donor antigen is sufficient to prevent stable transplant tolerance, rendering it unstable. Mechanistic studies revealed that recall antibody responses and memory CD8+ T cell expansion were initially controlled, but memory CD4+Foxp3- T cell (Tconv) responses were not. Remarkably, naive donor-specific Tconvs at tolerance induction also acquired a resistance to tolerance, proliferating and acquiring a phenotype similar to memory Tconvs. This phenomenon of "linked sensitization" underscores the challenges of reprogramming a primed immune response toward tolerance and identifies a potential therapeutic checkpoint for synergizing with costimulation blockade to achieve transplant tolerance in the clinic. |
