Mechanisms of regulatory T cell processes by IL-2

IL-2 调节 T 细胞过程的机制

• 批准号: 10490273
• 负责人: Acacia Nicole Crouch
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490273
• 关键词: ATAC-seq; Ablation; Acute; Address; Adoptive Transfer; Adrenal Cortex Hormones; Affect; American; Animals; Apoptosis; Autoimmune Diseases; Autoimmunity; Bioinformatics; Biological Assay; Biology; Bypass; Cause of Death; Cell physiology; Complex; Complication; Data; Defect; Development; Disease; Dose; Drops; Epigenetic Process; Evaluation; Exhibits; Fellowship; Flow Cytometry; Genetic Risk; Genetic Transcription; Heterogeneity; Homeostasis; Human; IL2RA gene; Immune; Incidence; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukin 2 Receptor; Interleukin-2; Investigation; Knock-out; Knockout Mice; Knowledge; Lead; Lupus; Malignant Neoplasms; Manipulative Therapies; Measures; Mediating; Memory; Metabolism; Modeling; Molecular; Mus; Mutation; Pathway interactions; Peripheral; Play; Population; Positioning Attribute; Prevention; Process; Receptor Signaling; Recombinant Interleukin-2; Regulatory T-Lymphocyte; Research; Role; Self Tolerance; Signal Transduction; Techniques; Therapeutic; Training; Transcription Process; Woman; autoreactive T cell; cytokine; experience; improved; in vitro Assay; in vivo; middle age; mouse model; mutant; overtreatment; peripheral tolerance; side effect; tool; transcriptome sequencing

Autoimmune disease is one of the leading causes of death for young and middle-aged women in the US. These diseases are mediated by autoreactive T cells, which are naturally contained by T regulatory cells (Tregs). Non-functional mutations in the IL-2 receptor (IL-2R) lead to autoimmunity due to deficiencies in Treg survival and function. This finding is corroborated by in vivo mouse models, leading to the widespread conclusion that IL-2 is important for Treg survival. However, recent data indicates this is oversimplified. Our lab studies a mouse model in which the alpha chain (CD25) of the IL-2R on peripheral Tregs is conditionally ablated. CD25 knockout Tregs demonstrate a disproportionate loss of central Tregs, which are long-lived circulating Tregs that give rise to effectors to maintain self-tolerance. Bulk knockout Tregs also display disruptions in critical Treg processes such as proliferation, survival, metabolism and suppressive function. Additionally, there is an absence of highly suppressive terminally differentiated Tregs in IL-2R mutant animals, indicating IL-2 may regulate the development of highly suppressive Tregs required for maintain peripheral tolerance. Given these findings, IL-2 signaling controls processes that are essential for the prevention of autoimmunity and understanding this role can provide therapeutic avenues to manipulate this population. Aim 1 will determine the effects of IL-2 on survival, proliferation, function and metabolism in Treg subsets. Using flow cytometry and in vitro assays, proliferation, apoptosis, survival, function and metabolism will be examined in Tregs subsets with and without IL-2 signaling. This aim will inform the extent to which IL-2 regulates cellular processes in Tregs subsets to further define the way by which IL-2 maintains Treg populations. Aim 2 will evaluate the role of IL-2 in Treg differentiation and heterogeneity. Due to defects observed in the differentiation of Tregs in the setting of IL-2, this aim will use adoptively transferred Treg subsets with and without IL-2 signaling to determine how IL-2 regulates development of eTregs from cTregs. Aim 3 will define the distinct IL-2 dependent transcriptional and epigenetic processes in cTregs versus eTregs. This aim will harness high throughput techniques such as RNAseq and ATAC-seq to correlate epigenetic and transcriptional changes as a consequence of IL-2 signaling, or lack thereof, in Treg subsets. By defining IL-2-dependent pathways and cellular processes that differ between them, these findings will be integrated with those in aim 1 to provide a clear role for IL-2 in regulating the cellular processes in each Treg subset. The main objective of this fellowship research is to define IL-2 driven processes coordinating Treg survival and homeostasis that are acutely relevant for understanding therapeutic applications of this cytokine and broadly relevant for understanding autoimmune disease.

自身免疫性疾病是美国中青年妇女死亡的主要原因之一。