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The Role of Nrf2 in Primary Human CD4 T Cell Activation and Differentiation
Author(s) -
Turley Alexandra E,
Zagorski Joseph,
Rockwell Cheryl E
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb621
Subject(s) - chemistry , microbiology and biotechnology , activator (genetics) , t cell , null cell , peripheral blood mononuclear cell , cd19 , immunology , oxidative stress , immune system , cell , biology , in vitro , biochemistry , receptor , gene
The transcription factor nuclear factor erythroid‐derived 2 like‐2 (Nrf2) responds to cell stress such as reactive oxygen species, electrophilic xenobiotics, and heavy metals. In response to such stress, Nrf2 induces a battery of detoxification, antioxidant, and metabolizing genes. In addition to its cytoprotective functions, Nrf2 has been implicated in immune modulation. Female Nrf2‐null mice develop a disease similar to systemic lupus erythematosus as they age. In addition, Nrf2‐null mice are more sensitive to a number of inflammatory stimuli such as cecal‐ligation and puncture and experimental autoimmune encephalomyelitis, and conversely, Nrf2 activation helps protect against these stimuli. Nrf2 has also been shown to modulate macrophage and dendritic cell function in vitro , and recently our lab has shown that Nrf2 skews CD4 T cell differentiation in primary mouse CD4 cells towards a Th2 phenotype. However, the function of Nrf2 in primary human CD4 T cell activation and differentiation remains unclear. Therefore, the purpose of these studies was to determine the role of Nrf2 in primary human CD4 T cell activation and differentiation. In these studies, peripheral blood mononuclear cells (PBMC) and CD4 cells were isolated from human blood. Cells were treated with either tert‐butylhydroquinone (tBHQ), a commonly used food additive and Nrf2 activator, or 1[2‐Cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]imidazole (CDDO‐IM), another Nrf2 activator, for 30min, then activated with anti‐CD3/anti‐CD28. Treatment of PBMCs with tBHQ for 6h increased expression of the Nrf2 target genes HMOX, GCLC, and NQO1. Both tBHQ and CDDO‐IM inhibited events of T cell activation at 24h, including production of the cytokines interleukin‐2 and interferon‐γ and expression of the cell surface markers CD25 and CD69. Isolated CD4 T cells show greater inhibition of early events following T cell activation in response to tBHQ as compared to PBMCs. tBHQ treatment increased production of the Th2 cytokines interleukin‐5, interleukin‐4, and interleukin‐13 at 120h by CD4 T cells after activation, and upon restimulation of these cells with anti‐CD3/anti‐CD28, indicating a potential effect on differentiation as well. Overall, these data indicate that Nrf2 inhibits primary human CD4 T cell activation, and potentially shifts differentiation towards a Th2 phenotype. Support or Funding Information (Supported by NIH grants ES018885 and ES007255).