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

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-gamma (IFN-gamma) 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-gamma resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in skin; and absence of both IFN-gamma 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-gamma-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.

• Authors: 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
• Journal: Blood (Blood) Vol. 114 Issue 14 Pg. 3101-12 (Oct 01 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 19602708 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• B7-1 Antigen
• B7-H1 Antigen
• Cd274 protein, mouse
• Interleukin-17
• Membrane Glycoproteins
• Peptides
• Interleukin-4
• Interferon-gamma

Topics

• Animals
• Antibodies, Monoclonal (immunology)
• B7-1 Antigen (physiology)
• B7-H1 Antigen
• CD4-Positive T-Lymphocytes (immunology, pathology)
• Cell Differentiation
• Cell Movement
• Flow Cytometry
• Graft vs Host Disease (immunology, metabolism, pathology)
• Idiopathic Interstitial Pneumonias (etiology, pathology)
• Interferon-gamma (physiology)
• Interleukin-17 (physiology)
• Interleukin-4
• Lung (immunology, pathology)
• Membrane Glycoproteins (physiology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Neutralization Tests
• Peptides (physiology)
• Skin (immunology, pathology)
• T-Lymphocytes, Helper-Inducer (immunology, pathology)
• Th1 Cells (immunology, pathology)
• Th2 Cells (immunology, pathology)