Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease.
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.
Yi
Tangsheng
T
The Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Chen
Ying
Y
Wang
Lin
L
Du
Gong
G
Huang
Daniel
D
Zhao
Dongchang
D
Johnston
Heather
H
Young
James
J
Todorov
Ivan
I
Umetsu
Dale T
DT
Chen
Lieping
L
Iwakura
Yoichiro
Y
Kandeel
Fouad
F
Forman
Stephen
S
Zeng
Defu
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018122:B7-1 Antigen / Q000502:physiology; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D054988:Idiopathic Interstitial Pneumonias / Q000209:etiology / Q000473:pathology; D007371:Interferon-gamma / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology; D015847:Interleukin-4; D008168:Lung / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009500:Neutralization Tests; D010455:Peptides / Q000502:physiology; D012867:Skin / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology*; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology*
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D020381:Interleukin-17; D008562:Membrane Glycoproteins; D010455:Peptides; D015847:Interleukin-4; D007371:Interferon-gamma