Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt

LSM Fulton, MJ Carlson, JM Coghill, LE Ott… - The Journal of …, 2012 - journals.aai.org
LSM Fulton, MJ Carlson, JM Coghill, LE Ott, ML West, A Panoskaltsis-Mortari, DR Littman
The Journal of Immunology, 2012journals.aai.org
Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic
stem cell transplantation. Previously, acute GVHD had been considered to be mediated
predominantly by Th1-polarized T cells. Recently, investigators have identified a second
proinflammatory lineage of T cells termed Th17 that is critically dependent on the
transcription factor retinoic acid-related orphan receptor (ROR) γt. In this study, we have
evaluated the role of Th17 cells in murine acute GVHD by infusing donor T cells lacking …
Abstract
Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR) γt. In this study, we have evaluated the role of Th17 cells in murine acute GVHD by infusing donor T cells lacking RORC and as a consequence the isoform RORγt. Recipients given donor CD4+ and CD8+ T cells lacking RORC had significantly attenuated acute GVHD and markedly decreased tissue pathology in the colon, liver, and lung. Using a clinically relevant haploidentical murine transplantation model, we showed that RORC−/− CD4+ T cells alone diminished the severity and lethality of acute GVHD. This was not found when CD4+ T cells from RORC−/− mice were given to completely mismatched BALB/c mice, and it was correlated with absolute differences in the generation of TNF in the colon after transplant. Thus, CD4+ T cell expression of RORC is important in the pathogenesis of acute GVHD.
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