Beyond Antioxidation: Keap1-Nrf2 in the Development and Effector Functions of Adaptive Immune Cells

Abstract

Ubiquitously expressed in mammalian cells, the Kelch-like ECH-associated protein 1 (Keap1)-NF erythroid 2-related factor 2 (Nrf2) complex forms the evolutionarily conserved antioxidation system to tackle oxidative stress caused by reactive oxygen species. Reactive oxygen species, generated as byproducts of cellular metabolism, were identified as essential second messengers for T cell signaling, activation, and effector responses. Apart from its traditional role as an antioxidant, a growing body of evidence indicates that Nrf2, tightly regulated by Keap1, modulates immune responses and regulates cellular metabolism. Newer functions of Keap1 and Nrf2 in immune cell activation and function, as well as their role in inflammatory diseases such as sepsis, inflammatory bowel disease, and multiple sclerosis, are emerging. In this review, we highlight recent findings about the influence of Keap1 and Nrf2 in the development and effector functions of adaptive immune cells, that is, T cells and B cells, and discuss the knowledge gaps in our understanding. We also summarize the research potential and targetability of Nrf2 for treating immune pathologies.

FIGURE 1.

Overview of the Keap1–Nrf2 pathway. Under homeostatic conditions, Nrf2, bound to a trimeric complex with Keap1 and Cullin3, is ubiquitinated and thence degraded by the 26S proteasome. During oxidative stress, the reactive cysteine residues in Keap1 bind to ROS or electrophilic toxins, causing a conformational change that impairs its ability to bind Nrf2. Nrf2 accumulates in the cytoplasm and then translocates into the nucleus where it activates the transcription of antioxidant-responsive genes. ARE, antioxidant response element; sMaf, small musculoaponeurotic fibrosarcoma. This figure was made in BioRender.com

FIGURE 2.

Nrf2 levels influence proinflammatory and anti-inflammatory responses by adaptive immune cells. The protein levels of Nrf2, negatively regulated by Keap1, play a deciding factor in T cell–mediated inflammatory responses. Nrf2 activation supports the differentiation of the Th2 subset, regulatory T cells (Tregs), and the NKT2 subset while inhibiting the differentiation of Th1, Th17, NKT1, and NKT17 subsets. Conversely, the absence of or low Nrf2 results in enhanced proinflammatory responses, characterized by the differentiation of Th1, Th17, NKT1, and NKT17 subsets, whereas subdued generation of Th2, Treg, and NKT2 subsets. Nrf2 activation levels also influence the generation of humoral responses. Whereas low Nrf2 levels favor T cell–dependent production of IgG and IgM Abs by activated B cells, high Nrf2 suppresses B cell responses such as the differentiation of germinal center B cells and plasma cells. Thus, Nrf2 negatively regulates T–cell mediated inflammatory responses and T-dependent B cell responses. This figure was made in BioRender.com.