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

1 Citation (Scopus)

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

Fingerprint

Graft vs Host Disease
Regulatory T-Lymphocytes
T-Lymphocytes
Cell Transplantation
Transplantation
Interleukin-23
Interleukin-17
Adoptive Transfer
Neutralizing Antibodies
Transcriptome
Interleukin-4
Interleukin-10
Immunosuppression
Thymus Gland
Intestines
Mortality

Keywords

  • Bone marrow transplantation
  • Immunology
  • Transplantation

Cite this

Yang, J., Ramadan, A., Reichenbach, D. K., Loschi, M., Zhang, J., Griesenauer, B., ... 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

Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host disease. / Yang, Jinfeng; Ramadan, Abdulraouf; Reichenbach, Dawn K.; Loschi, Michael; Zhang, Jilu; Griesenauer, Brad; Liu, Hong; Hippen, Keli L.; Blazar, Bruce R.; Paczesny, Sophie.

In: JCI Insight, Vol. 4, No. 5, 07.03.2019.

Research output: Contribution to journalArticle

Yang, J, Ramadan, A, Reichenbach, DK, Loschi, M, Zhang, J, Griesenauer, B, Liu, H, Hippen, KL, Blazar, BR & Paczesny, S 2019, 'Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host disease', JCI Insight, vol. 4, no. 5. https://doi.org/10.1172/jci.insight.122014
Yang, Jinfeng ; Ramadan, Abdulraouf ; Reichenbach, Dawn K. ; Loschi, Michael ; Zhang, Jilu ; Griesenauer, Brad ; Liu, Hong ; Hippen, Keli L. ; Blazar, Bruce R. ; Paczesny, Sophie. / Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host disease. In: JCI Insight. 2019 ; Vol. 4, No. 5.
@article{280f467002cb4ae2a60f81f2236f3e73,
title = "Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host disease",
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.",
keywords = "Bone marrow transplantation, Immunology, Transplantation",
author = "Jinfeng Yang and Abdulraouf Ramadan and Reichenbach, {Dawn K.} and Michael Loschi and Jilu Zhang and Brad Griesenauer and Hong Liu and Hippen, {Keli L.} and Blazar, {Bruce R.} and Sophie Paczesny",
year = "2019",
month = "3",
day = "7",
doi = "10.1172/jci.insight.122014",
language = "English (US)",
volume = "4",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host disease

AU - Yang, Jinfeng

AU - Ramadan, Abdulraouf

AU - Reichenbach, Dawn K.

AU - Loschi, Michael

AU - Zhang, Jilu

AU - Griesenauer, Brad

AU - Liu, Hong

AU - Hippen, Keli L.

AU - Blazar, Bruce R.

AU - Paczesny, Sophie

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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.

AB - 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.

KW - Bone marrow transplantation

KW - Immunology

KW - Transplantation

UR - http://www.scopus.com/inward/record.url?scp=85062635028&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062635028&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.122014

DO - 10.1172/jci.insight.122014

M3 - Article

C2 - 30694220

AN - SCOPUS:85062635028

VL - 4

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 5

ER -