Radiation and host retinoic acid signaling promote the induction of gut-homing donor T cells after allogeneic hematopoietic stem cell transplantation.

Intestinal graft-versus-host disease (GVHD) remains a devastating complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although it has been well established that gut-tropic donor T cells expressing integrin α4β7 are required to cause intestinal damage, the factors that control the induction of this pathogenic T cell population remain to be identified. Retinoic acid (RA) plays an important role in inducing α4β7 expression on T cells. In this study, we showed that gene expression of retinaldehyde dehydrogenase, the key enzyme involved in RA biosynthesis, is significantly increased in the spleen and mesenteric lymph nodes (MLNs) of irradiated mice. In a C57BL/6-into-B6D2F1 allogeneic HSCT model, irradiation significantly increased the induction of α4β7+ -donor T cells in mesenteric lymph nodes and spleen. Furthermore, we found that the RA pathway modulates the ability of dendritic cells to imprint gut-homing specificity on alloreactive T cells. We also showed that host dendritic cell RA signaling influences GVHD risk. Our studies identified radiation and recipient RA signaling as 2 primary factors that dictate the magnitude of gut-homing donor T cell induction after allogeneic HSCT. Attenuating radiation-associated inflammation and modulating host RA signaling represent feasible strategies to mitigate intestinal GVHD by reducing gut-seeking pathogenic donor T cells.