Dynamic JAK-STAT/IFN-signaling in subclinical to clinical T cell-mediated rejection following liver transplantation

ABSTRACT: Subclinical rejection after liver transplantation precludes immunosuppression withdrawal despite normal clinical function. To better understand the immunobiology of early subclinical rejection, we performed longitudinal, multimodal immune profiling and single-cell RNA-sequencing (scRNA-seq) in adult living-donor recipients (n=13) participating in an interventional immunosuppression withdrawal trial. Samples from patients with subclinical rejection (termed “nonpermissive”) at 12 months post-transplant exhibited distinct immune trajectories from those with quiescent (“permissive”) allografts, despite comparable baseline profiles. Central to these distinct dynamics was biphasic Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)-Interferon signaling. Greater interferon-stimulated gene (ISG) expression and JAK-STAT activation occurred post-reperfusion in permissive allograft recipients, which reversed at 12 months, when elevated ISG expression and JAK-STAT signaling was evident in nonpermissive recipients exhibiting subclinical rejection. We then leveraged our findings to ascertain whether a comparable signature existed in internal and external bulk RNA-seq and scRNA-seq liver transplant cohorts. Across cohorts, including a rodent model, there was a similar elevation in JAK-STAT signaling in instances of allograft rejection. We also detected distinct, portal-based phosphorylated STAT1 staining in a preliminary analysis of biopsies exhibiting histologic rejection compared with non-rejecting controls. Moreover, ruxolitinib-mediated JAK inhibition suppressed alloreactive CD8+ T cell proliferation and inflammatory-mediator production in vitro. Together, these exploratory findings suggest a temporal, biphasic role for JAK-STAT signaling in the regulation and occurrence of T cell-mediated rejection following liver transplant and highlight JAK inhibition as a potential therapeutic strategy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293039 | GEO | 2026/08/26

REPOSITORIES: GEO