Nrf2 regulates CD4+ T cell-induced acute graft-versus-host disease in mice.

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor that is well known for its role in regulating the cellular redox pathway. Although there is mounting evidence suggesting a critical role for Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role for Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2 -/- donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut-homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2 -/- donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2 -/- donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings characterized a previously unrecognized role for Nrf2 in T-cell function, as well as revealed a novel therapeutic target to improve the outcomes of allo-HCT.

[1]  S. Biswal,et al.  Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice , 2017, Molecular and Cellular Biology.

[2]  K. Liby,et al.  Nrf2-Dependent and -Independent Effects of tert-Butylhydroquinone, CDDO-Im, and H2O2 in Human Jurkat T Cells as Determined by CRISPR/Cas9 Gene Editing , 2017, The Journal of Pharmacology and Experimental Therapeutics.

[3]  Hongye Liu,et al.  Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells. , 2016, JCI insight.

[4]  A. Metidji,et al.  Helios Controls a Limited Subset of Regulatory T Cell Functions , 2016, The Journal of Immunology.

[5]  T. Holderried,et al.  Stable inhibitory activity of regulatory T cells requires the transcription factor Helios , 2015, Science.

[6]  S. Reddy,et al.  T Lymphocyte-Specific Activation of Nrf2 Protects from AKI. , 2015, Journal of the American Society of Nephrology : JASN.

[7]  F. Jiang,et al.  The antioxidant compound tert-butylhydroquinone activates Akt in myocardium, suppresses apoptosis and ameliorates pressure overload-induced cardiac dysfunction , 2015, Scientific Reports.

[8]  D. Sinclair,et al.  Aging-like Phenotype and Defective Lineage Specification in SIRT1-Deleted Hematopoietic Stem and Progenitor Cells , 2014, Stem cell reports.

[9]  O. Fardel,et al.  Nrf2 expression and activity in human T lymphocytes: stimulation by T cell receptor activation and priming by inorganic arsenic and tert-butylhydroquinone. , 2014, Free radical biology & medicine.

[10]  G. Altan-Bonnet,et al.  A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity. , 2014, Cancer discovery.

[11]  Zhiyong Guo,et al.  Advances in distinguishing natural from induced Foxp3(+) regulatory T cells. , 2013, International journal of clinical and experimental pathology.

[12]  C. Ebens,et al.  Blockade of individual Notch ligands and receptors controls graft-versus-host disease. , 2013, The Journal of clinical investigation.

[13]  Koichi Takahashi,et al.  Nrf2 regulates haematopoietic stem cell function , 2013, Nature Cell Biology.

[14]  D. MacEwan,et al.  The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance. , 2012, Blood.

[15]  Parmvir K Bahia,et al.  Neuroprotective effects of phenolic antioxidant tBHQ associate with inhibition of FoxO3a nuclear translocation and activity , 2012, Journal of neurochemistry.

[16]  M. Sporn,et al.  NRF2 and cancer: the good, the bad and the importance of context , 2012, Nature Reviews Cancer.

[17]  Johannes E. Schindelin,et al.  Fiji: an open-source platform for biological-image analysis , 2012, Nature Methods.

[18]  C. Klaassen,et al.  Th2 Skewing by Activation of Nrf2 in CD4+ T Cells , 2012, The Journal of Immunology.

[19]  M. Horowitz,et al.  Risk factors for acute GVHD and survival after hematopoietic cell transplantation. , 2012, Blood.

[20]  W. Wilson,et al.  Treatment-Induced Oxidative Stress and Cellular Antioxidant Capacity Determine Response to Bortezomib in Mantle Cell Lymphoma , 2011, Clinical Cancer Research.

[21]  D. MacEwan,et al.  High basal nuclear levels of Nrf2 in acute myeloid leukemia reduces sensitivity to proteasome inhibitors. , 2011, Cancer research.

[22]  Mario Roederer,et al.  Interpretation of cellular proliferation data: Avoid the panglossian , 2011, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[23]  R. Blasberg,et al.  Concurrent visualization of trafficking, expansion, and activation of T lymphocytes and T-cell precursors in vivo. , 2010, Blood.

[24]  DelindaA . Johnson,et al.  The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  Christopher G. King,et al.  The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease. , 2010, The Journal of clinical investigation.

[26]  C. B. Pickett,et al.  The Nrf2-Antioxidant Response Element Signaling Pathway and Its Activation by Oxidative Stress* , 2009, Journal of Biological Chemistry.

[27]  A. Kong,et al.  Molecular mechanisms of Nrf2‐mediated antioxidant response , 2009, Molecular carcinogenesis.

[28]  P. Wong,et al.  Dual roles of Nrf2 in cancer. , 2008, Pharmacological research.

[29]  C. Contag,et al.  Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. , 2008, Blood.

[30]  M. Bachmann,et al.  The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation. , 2008, Blood.

[31]  M. Tanimoto,et al.  FTY720 enhances the activation‐induced apoptosis of donor T cells and modulates graft‐versus‐host disease , 2007, European journal of immunology.

[32]  M. V. D. van den Brink,et al.  Absence of beta7 integrin results in less graft-versus-host disease because of decreased homing of alloreactive T cells to intestine. , 2006, Blood.

[33]  M. V. D. van den Brink,et al.  CCR2 is required for CD8-induced graft-versus-host disease. , 2005, Blood.

[34]  C. Contag,et al.  In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. , 2005, Blood.

[35]  W. Mitzner,et al.  Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice , 2005, The Journal of experimental medicine.

[36]  A. Hanash,et al.  Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. , 2005, Blood.

[37]  J. Mora,et al.  Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues , 2005, The Journal of experimental medicine.

[38]  J. Serody,et al.  In vivo imaging of graft-versus-host-disease in mice. , 2004, Blood.

[39]  A. Greenberg,et al.  LPAM (α4β7 integrin) is an important homing integrin on alloreactive T cells in the development of intestinal graft-versus-host disease , 2004 .

[40]  B. Malissen,et al.  Selective Generation of Gut Tropic T Cells in Gut-associated Lymphoid Tissue (GALT) , 2003, The Journal of experimental medicine.

[41]  C. Fathman,et al.  CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation , 2003, Nature Medicine.

[42]  Wolfgang Weninger,et al.  Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells , 2003, Nature.

[43]  E. Pamer,et al.  Feedback regulation of pathogen-specific T cell priming. , 2003, Immunity.

[44]  M. Kamm,et al.  Intestinal dendritic cells increase T cell expression of α4β7 integrin , 2002 .

[45]  P. Marrack,et al.  Linkage analysis of variations in CD4:CD8 T cell subsets between C57BL/6 and DBA/2 , 2002, Genes and Immunity.

[46]  E. Butcher,et al.  Rapid Acquisition of Tissue-specific Homing Phenotypes by CD4+ T Cells Activated in Cutaneous or Mucosal Lymphoid Tissues , 2002, The Journal of experimental medicine.

[47]  K. Kang,et al.  Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells. , 2001, Molecular pharmacology.

[48]  G. Holländer,et al.  Thymic atrophy in murine acute graft-versus-host disease is effected by impaired cell cycle progression of host pro-T and pre-T cells. , 2000, Blood.

[49]  C. Perreault,et al.  Massive Activation-Induced Cell Death of Alloreactive T Cells With Apoptosis of Bystander Postthymic T Cells Prevents Immune Reconstitution in Mice With Graft-Versus-Host Disease , 1999 .

[50]  J. Crawford,et al.  An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. , 1996, Blood.

[51]  Y. Kan,et al.  Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[52]  L. Picker,et al.  Control of lymphocyte recirculation in man. II. Differential regulation of the cutaneous lymphocyte-associated antigen, a tissue-selective homing receptor for skin-homing T cells. , 1993, Journal of immunology.

[53]  T. Ghayur,et al.  The Functional and Histological Basis for Graft‐versus‐Host‐Induced Immunosuppression , 1985, Immunological reviews.

[54]  J. Sprent,et al.  Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow , 1978, The Journal of experimental medicine.

[55]  T. Seemayer,et al.  Thymic involution in murine graft-versus-host reaction. Epithelial injury mimicking human thymic dysplasia. , 1977, The American journal of pathology.