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

• Published in: The Journal of immunology (1950) 2012-08, Vol.189 (4), p.1765-1772
• Main Authors: Fulton, LeShara M, Carlson, Michael J, Coghill, James M, Ott, Laura E, West, Michelle L, Panoskaltsis-Mortari, Angela, Littman, Dan R, Blazar, Bruce R, Serody, Jonathan S
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology; Real-Time Polymerase Chain Reaction; Th17 Cells - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200858

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.