Keap1-Nrf2 regulate nutrient metabolism to direct CD4⁺ T-cell activation and inflammatory functions.

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B692
Abstract ID: 4506

Presenting Author:
Kalyani Pyaram , Assistant Professor at Univ. of Kansas Med. Ctr.

Abstract:

CD4⁺T-cells are critical orchestrators of antigen-specific adaptive immunity. Here we elucidate the role of nuclear factor erythroid 2–related factor2 (Nrf2), negatively regulated by Kelch-like ECH-associated protein (Keap1), beyond the traditional oxidative stress regulation, in modulating the effector responses of CD4⁺ T-cells by influencing their nutrient metabolism. We noted that in CD4⁺ T-cells, Nrf2 protein levels increase during early activation but decrease during their expansion. With the objective of identifying the effect of T-cell intrinsic Nrf2, we used T-cell specific knockout (KO) mice of Keap1 or Nrf2. In vitro CD4⁺ T-cell activation and Th subset differentiation assays were performed, and the findings were validated in vivo. Constitutively high Nrf2 in activated CD4⁺ T-cells lead to increased proliferation as well as apoptosis, increased expression of early activation markers and augmented TCR signaling in addition to dampened Th1 differentiation yet elevated Foxp3⁺Treg generation. Further, Nrf2-high Keap1-KO CD4⁺ T-cells caused a milder disease in mouse models of inflammatory bowel disease than WT or Nrf2-KO cells. Mechanistically, Nrf2 drives glutaminolysis to support increased proliferative capacity but inhibits glycolysis in CD4⁺ T-cells. Overall, our data uncover a novel role of Nrf2 as a metabolic modulator of activation driven expansion and inflammatory function of CD4⁺ T-cells, thus providing a framework for improving Nrf2-targeting drugs.