Novel Requirements for Akt1 in T Cell Commitment

T 细胞承诺中对 Akt1 的新要求

• 批准号: 10077817
• 负责人: Yina Hsing Huang
• 金额: $ 45.73万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077817
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Acute T Cell Leukemia; Adaptive Immune System; Address; Affect; Attention; Attenuated; B-Lymphocytes; Binding; CD8B1 gene; Cell Line; Cell Lineage; Cell Survival; Cell membrane; Cells; Couples; Cytokine Receptors; Defect; Dependence; Development; Disease; Dose; ES01; Ensure; FRAP1 gene; Family; Feedback; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Homologous Protein; Hyperactivity; Immunologic Deficiency Syndromes; Inositol; Investigation; Kinetics; Lead; Ligands; Lipids; Malignant Epithelial Cell; Mediating; Membrane; Metabolic; Metabolism; Modeling; PDPK1 gene; PH Domain; PTEN gene; Pathologic; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Polyphosphates; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Readiness; Regulatory T-Lymphocyte; Role; Signal Transduction; Structure; Surface; T cell activating factor; T cell regulation; T cell transcription factor 1; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Thymocyte Development; Thymus Gland; Time; To specify; Transcript; Transcription Coactivator; Transcriptional Regulation; alpha-beta T-Cell Receptor; attenuation; beta catenin; cell growth; cell type; gene product; glucose metabolism; member; notch protein; novel; premature; preservation; progenitor; receptor; recruit; thymocyte; transcription factor

ABSTRACT Akt1, Akt2 and Akt3 are members of a family of serine/threonine kinases that are key effectors of PI3K. The Akt family has been well characterized to promote cell survival, glucose metabolism and proliferation in many cell types including developing T cells. Thymocytes express all Akt isoforms to varying degrees. Ablation of single or multiple Akt genes results in differential blocks in T cell development. Loss of all three Akt isoforms leads to an early developmental defect due to decreased survival of CD4–CD8– double negative (DN) thymocytes. Expression of Akt2 or Akt3 alone is sufficient to preserve DN survival; however, DN3 differentiation and DN4 thymocyte proliferation remain defective along with survival of cells at later developmental stages. These distinct phenotypes suggest either that different Akt isoforms regulate distinct functions or that different doses of Akt activity are required to promote stage-specific cell survival, proliferation and differentiation. With no current evidence for isoform-specific functions, we focused our attention on characterizing mechanisms for regulating the dose of Akt activity. Surface receptors, including (pre-)T cell receptor and cytokine receptors, activate PI3K to generate PIP3. Interactions between PIP3 and the Pleckstrin homology (PH) domain of Akt are required to recruit Akt to the plasma membrane for activation. Thus, fine control of PI3K activity and PIP3 availability can directly regulate Akt activation levels. This application addresses an increasingly important alternative mechanism for indirectly controlling Akt activity: via generation of IP4, a soluble inositol polyphosphate that is structurally similar to PIP3. IP4 is generated following (pre)TCR stimulation and competes with PIP3 for binding to the Akt PH domain. Thymocytes deficient in IP4 activate Akt excessively following expression of preTCR at the DN3 and DN4 stages. Strikingly, Akt hyperactivity leads to accelerated β selection, premature reprogramming to glycolytic metabolism and loss of Notch dependency. This leads us to propose the global hypotheses that 1) preTCR- induced IP4 generation restricts Akt-dependent metabolic reprogramming and proliferation to ensure adequate Notch signaling and 2) preTCR and Notch cooperative signaling is required for T cell lineage specification. Successful completion of this study will shift our current understanding of T lineage specification by revealing 1) an unexpected requirement for preTCR in imposing a Notch checkpoint and in co-stimulating Notch function, 2) a novel preTCR feedback mechanism that controls DN thymocyte proliferation/maturation via tuning of Akt activity and metabolic reprogramming; and 3) a non-canonical pathway for activating TCF1-dependent transcription to specify T cell commitment.

抽象的 AKT1，AKT2和AKT3是PI3K的关键作用的丝氨酸/苏氨酸激酶家族的成员。这 AKT家族的特征是促进细胞存活，葡萄糖代谢和增殖 许多细胞类型，包括开发T细胞。胸腺细胞以不同程度表达所有Akt同工型。 单个或多个AKT基因的消融导致T细胞发育中的差异。损失这三个 AKT同工型导致由于CD4 – CD8-双重生存率降低而导致早期发育缺陷 阴性（DN）胸腺细胞。仅AKT2或AKT3的表达就足以保留DN存活。然而， DN3分化和DN4胸腺细胞的增殖以及细胞的存活在后来保持有缺陷 发展阶段。这些独特的表型表明，要么不同的Akt同工型调节不同 功能或需要不同剂量的Akt活性来促进特异性细胞存活， 增殖和分化。目前没有同类特异性功能的证据，我们集中于我们的 注意表征确定AKT活性剂量的机制。表面受体，包括 （前）T细胞受体和细胞因子受体，激活PI3K以生成PIP3。 pip3和 需要Akt的Pleckstrin同源（pH）域才能募集Akt到质膜 激活。这是对PI3K活性和PIP3可用性的精细控制可以直接调节Akt激活水平。 该应用程序解决了间接控制AKT的越来越重要的替代机制 活性：通过产生IP4，这是一种与PIP3结构相似的固体肌醇聚磷酸盐。 IP4是 生成以下（前）TCR刺激，并与PIP3竞争与Akt pH结构域结合。 在DN3和DN4上表达了Pretcr后，胸腺细胞不足于IP4激活Akt 阶段。令人惊讶的是，AKT多动症导致β选择加速，过早重编程至糖酵解 代谢和缺口依赖性的丧失。这使我们提出了全球假设，即1） 诱导的IP4生成限制了依赖AKT的代谢重编程和增殖，以确保 T细胞谱系需要足够的Notch信号和2）Pretcr和Notch教练信号传导 规格。这项研究的成功完成将改变我们当前对T血统的理解 通过揭示1）在施加缺口检查点和在 共同刺激缺口函数，2）控制DN胸腺细胞的新型假定反馈机制 通过调整AKT活性和代谢重编程，增殖/成熟； 3）非典型的 激活TCF1依赖性转录以指定T细胞承诺的途径。

项目成果

Mst1 directs Myosin IIa partitioning of low and higher affinity integrins during T cell migration.

• DOI: 10.1371/journal.pone.0105561
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Xu X;Jaeger ER;Wang X;Lagler-Ferrez E;Batalov S;Mathis NL;Wiltshire T;Walker JR;Cooke MP;Sauer K;Huang YH
• 通讯作者: Huang YH

Mst1 Kinase Regulates the Actin-Bundling Protein L-Plastin To Promote T Cell Migration.

• DOI: 10.4049/jimmunol.1600874
• 发表时间: 2016-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Xu X;Wang X;Todd EM;Jaeger ER;Vella JL;Mooren OL;Feng Y;Hu J;Cooper JA;Morley SC;Huang YH
• 通讯作者: Huang YH

Diverse Roles of Akt in T cells.

• DOI: 10.20900/immunometab20210007
• 发表时间: 2021-01-01
• 期刊: Immunometabolism
• 作者: Abdullah, Leena;Hills, L Benjamin;Huang, Yina H
• 通讯作者: Huang, Yina H

Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease.

• DOI: 10.1158/2326-6066.cir-15-0015
• 发表时间: 2015-08
• 期刊: Cancer immunology research
• 影响因子: 10.1
• 作者: Clancy-Thompson E;Perekslis TJ;Croteau W;Alexander MP;Chabanet TB;Turk MJ;Huang YH;Mullins DW
• 通讯作者: Mullins DW

Resident memory T cells in the skin mediate durable immunity to melanoma.

• DOI: 10.1126/sciimmunol.aam6346
• 发表时间: 2017-04-14
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Malik BT;Byrne KT;Vella JL;Zhang P;Shabaneh TB;Steinberg SM;Molodtsov AK;Bowers JS;Angeles CV;Paulos CM;Huang YH;Turk MJ
• 通讯作者: Turk MJ