Retinoic acid–responsive CD8 effector T cells are selectively increased in IL-23–rich tissue in gastrointestinal GVHD

Abstract Gastrointestinal (GI) graft-versus-host disease (GVHD) is a major barrier in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The metabolite retinoic acid (RA) potentiates GI-GVHD mice via alloreactive T cells expressing the RA receptor-α (RARα), but role of RA-responsive human remains undefined. Therefore, we used conventional and novel sequential immunostaining flow cytometry to scrutinize tissues blood patients who had received allo-HSCT characterize impact on T-cell alloresponses. Expression RARα by mononuclear was increased after exposure RA. RARαhi were tissue, contained more cellular RA-binding proteins, localized with tissue damage, correlated GVHD severity mortality. By using targeted candidate protein approach, predicted phenotype context microenvironmental interleukin-23 (IL-23). Sequential confirmed presence population CD8 that coexpressed effector transcription factor T-bet IL-23–specific receptor (IL-23R). These GI- not skin-GVHD also selectively expanded GI-GVHD. Finally, functional approaches demonstrated predominantly GI-tropic cells, including identified vivo. IL-23–rich conditions potentiated this effect increasing β7 integrin expression reducing CD4 regulatory phenotype. In summary, have distinctive represents potential new therapeutic target.