Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host disease

Jinfeng Yang, Abdulraouf Ramadan, Dawn K. Reichenbach, Michael Loschi, Jilu Zhang, Brad Griesenauer, Hong Liu, Keli L. Hippen, Bruce R. Blazar, Sophie Paczesny

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Soluble stimulation-2 (ST2) is increased during graft-versus-host disease (GVHD), while Tregs that express ST2 prevent GVHD through unknown mechanisms. Transplantation of Foxp3- T cells and Tregs that were collected and sorted from different Foxp3 reporter mice indicated that in mice that developed GVHD, ST2+ Tregs were thymus derived and predominantly localized to the intestine. ST2-/- Treg transplantation was associated with reduced total intestinal Treg frequency and activation. ST2-/- versus WT intestinal Treg transcriptomes showed decreased Treg functional markers and, reciprocally, increased Rorc expression. Rorc-/- T cells transplantation enhanced the frequency and function of intestinal ST2+ Tregs and reduced GVHD through decreased gut-infiltrating soluble ST2-producing type 1 and increased IL-4/IL-10-producing type 2 T cells. Cotransfer of ST2+ Tregs sorted from Rorc-/- mice with WT CD25-depleted T cells decreased GVHD severity and mortality, increased intestinal ST2+KLRG1+ Tregs, and decreased type 1 T cells after transplantation, indicating an intrinsic mechanism. Ex vivo IL-33-stimulated Tregs (TregIL-33) expressed higher amphiregulin and displayed better immunosuppression, and adoptive transfer prevented GVHD better than control Tregs or TregIL-33 cultured with IL-23/IL-17. Amphiregulin blockade by neutralizing antibody in vivo abolished the protective effect of TregIL-33. Our data show that inverse expression of ST2 and RORγt in intestinal Tregs determines GVHD and that TregIL-33 has potential as a cellular therapy avenue for preventing GVHD.

Original languageEnglish (US)
JournalJCI Insight
Volume4
Issue number5
DOIs
StatePublished - Mar 7 2019

Keywords

  • Bone marrow transplantation
  • Immunology
  • Transplantation

ASJC Scopus subject areas

  • Medicine(all)

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    Yang, J., Ramadan, A., Reichenbach, D. K., Loschi, M., Zhang, J., Griesenauer, B., Liu, H., Hippen, K. L., Blazar, B. R., & Paczesny, S. (2019). Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host disease. JCI Insight, 4(5). https://doi.org/10.1172/jci.insight.122014