Regulatory T cells rely on CD71 expression for metabolic stability in specific tissues 9360

Abstract Description Regulatory T cells (Tregs) are a subset of CD4 T helper cells that combat autoimmune diseases. Treg function relies on a distinct cellular metabolism, distinguishing them from pro-inflammatory T cells. We showed that targeting the transferrin receptor for iron, CD71, depleted pro-inflammatory T cells while promoting Tregs and their Foxp3 expression. However, CD71-knockout (KO) in Tregs is lethal in mice. These mice develop spontaneous autoimmunity similar to scurfy mice, and show defective perinatal Treg expansion. Despite this phenotype, it is unclear whether KO Tregs retain any suppressive capacity or simply fail to proliferate. We tested the suppressive function of KO Tregs in a colitis model. CD71-KO Tregs significantly reduced disease pathology in the colon compared to mice that received no Tregs, although not as effectively as WT Tregs. Foxp3YFP-Cre-mediated deletion of CD71 in immunocompetent mice results in tissue-specific inflammation. The colon, kidney, and pancreas of mice with KO Tregs appeared healthy, whereas skin and lung tissue were severely inflamed. RNA-sequencing and flow cytometry analyses revealed that in affected tissues, KO Tregs are unstable, adopting T-bet and RORγt expression in addition to Foxp3. These KO Tregs also exhibit elevated Nrf2 signaling indicative of high oxidative stress and adopt a metabolism high in glycolysis. Thus, Tregs rely on CD71 for their stability and function at specific tissue sites such as the lung but not the colon. Funding Sources K.V. is supported by the Breakthrough T1D Advanced Postdoctoral Fellowship. Topic Categories Basic Autoimmunity (BA)