Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease

Tangsheng Yi, Ying Chen, Lin Wang, Gong Du, Daniel Huang, Dongchang Zhao, Heather Johnston, James Young, Ivan Todorov, Dale T. Umetsu, Lieping Chen, Yoichiro Iwakura, Fouad Kandeel, Stephen Forman, Defu Zeng

Research output: Contribution to journalArticle

Abstract

In acute graft-versus-host disease (GVHD), naive donor CD4+ T cells recognize alloantigens on host antigen-presenting cells and differentiate into T helper (Th) subsets (Th1, Th2, and Th17 cells), but the role of Th subsets in GVHD pathogenesis is incompletely characterized. Here we report that, in an MHC-mismatched model of C57BL/6 donor to BALB/c recipient, WT donor CD4+ T cells predominantly differentiated into Th1 cells and preferentially mediated GVHD tissue damage in gut and liver. However, absence of interferon-γ (IFN-γ) in CD4+ T cells resulted in augmented Th2 and Th17 differentiation and exacerbated tissue damage in lung and skin; absence of both IL-4 and IFN-γ resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in skin; and absence of both IFN-γ and IL-17 led to further augmentation of Th2 differentiation and idiopathic pneumonia. The tissue-specific GVHD mediated by Th1, Th2, and Th17 cells was in part associated with their tissue-specific migration mediated by differential expression of chemokine receptors. Furthermore, lack of tissue expression of the IFN-γ-inducible B7-H1 played a critical role in augmenting the Th2-mediated idiopathic pneumonia. These results indicate donor CD4+ T cells can reciprocally differentiate into Th1, Th2, and Th17 cells that mediate organ-specific GVHD.

Original languageEnglish (US)
Pages (from-to)3101-3112
Number of pages12
JournalBlood
Volume114
Issue number14
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Yi, T., Chen, Y., Wang, L., Du, G., Huang, D., Zhao, D., Johnston, H., Young, J., Todorov, I., Umetsu, D. T., Chen, L., Iwakura, Y., Kandeel, F., Forman, S., & Zeng, D. (2009). Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood, 114(14), 3101-3112. https://doi.org/10.1182/blood-2009-05-219402