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 ( MLN s) of irradiated mice. In a C57 BL /6‐into‐B6D2F1 allogeneic HSCT model, irradiation significantly increased the induction of α4β7 + ‐donor T cells in mesenteric lymph node s 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.