Nrf2 activation skews murine and human CD4 T cell differentiation towards a Th2 phenotype

Abstract

Abstract CD4 T cell differentiation is a critical part of the adaptive immune response during which CD4 T cells adapt a response to a specific pathogen. Nuclear factor erythroid-derived 2 like-2 (Nrf2) is a cell-stress responsive transcription factor that regulates a battery of antioxidant, detoxification, and cytoprotective genes. Nrf2 is activated by stressors such as reactive oxygen species and electrophilic xenobiotics, including tert-butylhydroquinone (tBHQ), a commonly used food preservative. Nrf2 has been shown to be immunomodulatory: Nrf2 null mice are more susceptible to inflammatory stimuli such as sepsis, lung injury, and experimental autoimmune encephalomyelitis. In addition, Nrf2 has been shown to modulate dendritic cell and macrophage function, however, the role of Nrf2 in CD4 T cells remains only partially characterized. Thus, the goal of the present studies is to determine the role of Nrf2 in CD4 T cell differentiation in primary human and mouse CD4 T cells. Treatment with the Nrf2 activator tBHQ increased production of the Th2 cytokines IL-4, IL-5, and IL-13 in CD4 T cells isolated from wild-type, but not Nrf2-null mice, and decreased production of the Th1 cytokine IFNγ. tBHQ increased GATA-3 and decreased T-bet DNA binding in wild type but not Nrf2-null mice. In primary human CD4 T cells, tBHQ treatment increased production of the cytokines IL-4, IL-5, and IL-13, and had no effect on IFNγ production upon restimulation. Collectively, these data suggest that Nrf2 activation promotes Th2 differentiation of primary human and mouse CD4 T cells. (Funded by NIH grants ES018885 and ES007255).