ST2/MyD88 deficiency protects mice against acute graft-versus-host disease and spares regulatory T cells

Brad Griesenauer, Hua Jiang, Jinfeng Yang, Jilu Zhang, Abdulraouf M. Ramadan, Jane Egbosiuba, Khaled Campa, Sophie Paczesny

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (HCT). Plasma levels of soluble membrane-bound ST2 (ST2) are elevated in human and murine aGVHD and correlated to type 1 T cells response. ST2 signals through the adapter protein MyD88. The role of MyD88 in T cells during aGVHD has yet to be elucidated. We found that knocking out MyD88 in the donor T cells protected against aGVHD independent of IL-1R and TLR4 signaling in two murine HCT models. This protection was entirely driven by MyD882/2 CD4 T cells. Transplanting donor MyD882/2 conventional T cells (Tcons) with wild-type (WT) or MyD882/2 regulatory T cells (Tregs) lowered aGVHD severity and mortality. Transcriptome analysis of sorted MyD882/2 CD4 T cells from the intestine 10 d post-HCT showed lower levels of Il1rl1 (gene of ST2), Ifng, Csf2, Stat5, Batf, and Jak2. Transplanting donor ST22/2 Tcons with WT or ST22/2 Tregs showed a similar phenotype with what we observed when using donor MyD882/2 Tcons. Decreased ST2 was confirmed at the protein level with less secretion of soluble ST2 and more expression of ST2 compared with WT T cells. Our data suggest that Treg suppression from lack of MyD88 signaling in donor Tcons during alloreactivity uses the ST2 but not the IL-1R or TLR4 pathways, and ST2 represents a potential aGVHD therapeutic target sparing Tregs.

Original languageEnglish (US)
Pages (from-to)3053-3064
Number of pages12
JournalJournal of Immunology
Volume202
Issue number10
DOIs
StatePublished - May 15 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Griesenauer, B., Jiang, H., Yang, J., Zhang, J., Ramadan, A. M., Egbosiuba, J., Campa, K., & Paczesny, S. (2019). ST2/MyD88 deficiency protects mice against acute graft-versus-host disease and spares regulatory T cells. Journal of Immunology, 202(10), 3053-3064. https://doi.org/10.4049/jimmunol.1800447