Identification of stem cell transcriptional programs normally expressed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease.
A hallmark of graft-versus-host-disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is the cytopathic injury of host tissues mediated by persistent alloreactive effector T cells (T(E)). However, the mechanisms that regulate the persistence of alloreactive T(E) during GVHD remain largely unknown. Using mouse GVHD models, we demonstrate that alloreactive CD8(+) T(E) rapidly diminished in vivo when adoptively transferred into irradiated secondary congenic recipient mice. In contrast, although alloreactive CD8(+) T(E) underwent massive apoptosis upon chronic exposure to alloantigens, they proliferated in vivo in secondary allogeneic recipients, persisted, and caused severe GVHD. Thus, the continuous proliferation of alloreactive CD8(+) T(E), which is mediated by alloantigenic stimuli rather than homeostatic factors, is critical to maintaining their persistence. Gene expression profile analysis revealed that although alloreactive CD8(+) T(E) increased the expression of genes associated with cell death, they activated a group of stem cell genes normally expressed in embryonic and neural stem cells. Most of these stem cell genes are associated with cell cycle regulation, DNA replication, chromatin modification, and transcription. One of these genes, Ezh2, which encodes a chromatin modifying enzyme, was abundantly expressed in CD8(+) T(E). Silencing Ezh2 significantly reduced the proliferation of alloantigen-activated CD8(+) T cells. Thus, these findings identify that a group of stem cell genes could play important roles in sustaining terminally differentiated alloreactive CD8(+) T(E) and may be therapeutic targets for controlling GVHD.
Kato
Koji
K
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-5942, USA.
Cui
Shuaiying
S
Kuick
Rork
R
Mineishi
Shin
S
Hexner
Elizabeth
E
Ferrara
James L M
JL
Emerson
Stephen G
SG
Zhang
Yi
Y
D053687:Adult Stem Cells / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D016026:Bone Marrow Transplantation; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D049109:Cell Proliferation / Q000187:drug effects; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D053595:Embryonic Stem Cells / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D015870:Gene Expression / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D006086:Graft vs Host Disease / Q000276:immunology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015851:Interleukin-7 / Q000494:pharmacology; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063151:Polycomb Repressive Complex 2; D034622:RNA Interference; D013234:Stem Cells / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D018106:CD28 Antigens; D017252:CD3 Complex; C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; D015851:Interleukin-7; D007519:Isoantigens; D007371:Interferon-gamma; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2