Abstract
IL-2R signaling is essential for regulatory T cell (Treg) function. However, the precise contribution of IL-2 during Treg thymic development, peripheral homeostasis and lineage stability remains unclear. Here we show that IL-2R signaling is required by thymic Tregs at an early step for expansion and survival, and a later step for functional maturation. Using inducible, conditional deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling is indispensable for Treg homeostasis, whereas Treg lineage stability is largely IL-2-independent. CD25 knockout peripheral Tregs have increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2R transcriptional signature is noted for thymic Tregs versus peripheral Tregs. These data indicate that IL-2R signaling in the thymus and the periphery leads to distinctive effects on Treg function, while peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation.
Highlights
IL-2R signaling is essential for regulatory T cell (Treg) function
These genetic tools have advanced our understanding of Treg function, they have not yet established the Treg-selective role of IL-2R signaling in the thymus, including the possibility of redundancy with IL-15 or inflammatory signals that are present in the context of autoimmune disease
We produced CD25 conditional knockout mice to assess the basis for this lethal disease and directly define the role of IL-2R signaling for Treg thymic development and peripheral homeostasis
Summary
IL-2R signaling is essential for regulatory T cell (Treg) function. the precise contribution of IL-2 during Treg thymic development, peripheral homeostasis and lineage stability remains unclear. Correspondence and requests for materials should be addressed to T.R. IL-2R signaling is essential for regulatory T cells (Tregs) in part by driving activation of STAT5 that directly upregulates Foxp[3] and CD25 in a positive feedback loop to establish and maintain Treg transcriptional identity[1,2,3]. IL-2R signaling is essential for regulatory T cells (Tregs) in part by driving activation of STAT5 that directly upregulates Foxp[3] and CD25 in a positive feedback loop to establish and maintain Treg transcriptional identity[1,2,3] Through this pathway, IL-2 promotes the maturation of CD4+ Foxp3lo T cells into CD4+ CD25+ Foxp3hi Tregs during thymic development[4,5,6]. Our study identifies overlapping but differential IL-2Rdependent functions for Treg thymic development and peripheral Treg homeostasis
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