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Distinct contributions of CCR4 versus CCR7 to thymocyte localization and central tolerance

CCR4 与 CCR7 对胸腺细胞定位和中枢耐受的独特贡献

基本信息

批准号：
10411920
负责人：
Lauren Ilyse Richie EHRLICH
金额：
$ 47.22万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10411920
关键词：
Agonist Antigen Receptors Antigen-Presenting Cells Antigens Autoantigens Autoimmunity Automobile Driving Biological Assay Blood Bone Marrow CC chemokine receptor 4 CD69 antigen Cell Survival Cells Chimera organism Dangerousness Data Dendritic Cells Ensure Funding Genetic Impairment Individual Life Ligands Malignant Neoplasms Mature Thymocyte Mediating Modeling Molecular Mosaicism Peripheral Play Process Proteins Proteome Regulatory T-Lymphocyte Reporting Role Scanning Self Tolerance Structure of thymic medulla T cell receptor repertoire sequencing T-Lymphocyte T-cell receptor repertoire Testing Thymic epithelial cell Thymocyte Selection Thymus Gland Tissues autoreactive T cell autoreactivity base central tolerance chemokine receptor combat differential expression experimental study innovation mouse model novel pathogen prevent receptor expression thymocyte two photon microscopy

项目摘要

ABSTRACT After undergoing positive selection in the cortex, thymocytes migrate into the medulla where central tolerance is enforced by antigen presenting cells (APCs) displaying a diverse array of auto-antigens. Dendritic cells (DCs) and medullary thymic epithelial cells (mTECs) are the two predominant medullary APCs that induce central tolerance. Collectively, mTECs express the majority of the proteome, but any individual self- antigen is expressed by only 1-3 % of these cells. Thymic DCs present self-antigens derived not only from their own proteome, but also those acquired from the blood, from mTECs, and from peripheral tissues. Thus, mTECs and DCs display a mosaic of self-antigens, which thymocytes must navigate to scan for auto-reactivity. This process is critical for self-tolerance, as lost expression of even one self-antigen in the thymus can result in peripheral autoimmunity. In this proposal, we will investigate mechanisms by which the chemokine receptors CCR4 and CCR7 alter thymocyte localization and interactions with distinct APCs to enforce central tolerance. It is well-documented that CCR7 promotes thymocyte medullary localization and thus, negative selection. Over the last funding period, we identified a critical role for CCR4 in these processes as well. Our data suggest a novel model in which CCR4 promotes medullary entry of post-positive selection thymocytes and interactions with DCs, while CCR7 sustains medullary localization of mature thymocytes and promotes interactions mTECs, to induce negative selection and Treg differentiation of distinct TCR repertoires. In Aim 1, we will use a combination of 2-photon microscopy, TCR repertoire sequencing, and TCR retrogenic bone marrow chimeras to test the impact of CCR4 and CCR7 on thymocyte localization, interactions with APCs, and central tolerance. Notably, we have developed a novel 2-photon microscopy approach to quantify the contribution of distinct APCs to negative selection, and will expand this approach to identify APCs required for Treg selection. Our recent data also suggest that both early and late stages of negative selection occur in the medulla, driven by CCR4 and CCR7, respectively. In Aim 2, we will test this novel model, which contrasts with the prevailing view that early and late stages of selection occur in the cortex and medulla, respectively. Over the last funding period, we identified a novel role for CCR7 expression by thymic DCs in regulating Treg selection. In Aim 3, we will use existing and novel genetic mouse models, functional assays, TCR repertoire sequencing, and retrogenic bone marrow chimeras to test the hypothesis that CCR7 expression by thymic DCs promotes their survival and is required for acquisition and display of mTEC-derived self-antigens, thus impacting repertoire selection. Altogether, the proposed experiments will elucidate mechanisms by which CCR4 and CCR7 promote central tolerance and will test the innovative model, suggested by our data, that central tolerance is separated into two stages, first dominated by DC-mediated deletion of less mature thymocytes, and then by mTEC-mediated deletion of mature thymocytes to ensure self- tolerance.

摘要在皮质中经历阳性选择后，胸腺细胞迁移到髓质中，耐受性通过展示多种自身抗原的抗原呈递细胞（APC）来增强。树突状细胞（DC）和胸腺髓质上皮细胞（mTEC）是诱导免疫应答的两种主要的髓质APC。中央宽容总的来说，mTEC表达大部分蛋白质组，但任何个体的自身抗原都是仅由这些细胞的1- 3%表达。胸腺DC呈递自身抗原，蛋白质组，但也从血液中获得的，从mTEC，和从外周组织。因此，mTEC DC显示自身抗原的镶嵌，胸腺细胞必须导航以扫描自身反应性。这这一过程对于自身耐受性至关重要，因为胸腺中即使一种自身抗原的表达缺失也会导致外周自身免疫在这个提议中，我们将研究趋化因子受体 CCR 4和CCR 7改变胸腺细胞定位和与不同APC的相互作用以增强中枢耐受性。有充分证据表明，CCR 7促进胸腺细胞髓质定位，因此，CCR 7对胸腺细胞髓质定位呈阴性。选择.在上一个资助期间，我们也确定了CCR 4在这些过程中的关键作用。我们数据提示了一种新的模型，其中CCR 4促进阳性选择后胸腺细胞的髓质进入和与DC的相互作用，而CCR 7维持成熟胸腺细胞的髓质定位，并促进通过与mTEC相互作用，以诱导不同TCR库的负选择和Treg分化。在目标1中，我们将结合使用双光子显微镜、TCR库测序和TCR逆转录骨骨髓嵌合体，以测试CCR 4和CCR 7对胸腺细胞定位、与APC的相互作用以及中央宽容值得注意的是，我们已经开发了一种新的双光子显微镜方法来量化不同的APC对阴性选择的贡献，并将扩大这种方法，以确定所需的APC Treg选择。我们最近的数据还表明，负选择的早期和晚期都发生在髓质，分别由CCR 4和CCR 7驱动。在目标2中，我们将测试这个新模型，它与普遍的观点认为，选择的早期和晚期阶段分别发生在皮质和髓质。超过在上一个资助期，我们确定了胸腺DCs表达CCR 7在调节Treg中的新作用，选择.在目标3中，我们将使用现有的和新的遗传小鼠模型，功能测定，TCR库，测序和逆转录骨髓嵌合体，以检验胸腺DCs的CCR 7表达促进它们的存活，并且是获得和展示mTEC衍生的自身抗原所必需的，因此影响库选择。总之，拟议的实验将阐明机制， CCR 4和CCR 7促进中枢耐受性，并将测试我们的数据所建议的创新模型，中心耐受分为两个阶段，第一阶段由DC介导的较不成熟的缺失主导，然后通过mTEC介导的成熟胸腺细胞的缺失来确保自身耐受性。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dynein Separately Partners with NDE1 and Dynactin To Orchestrate T Cell Focused Secretion.

DOI：
10.4049/jimmunol.1600180
发表时间：
2016-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Nath S;Christian L;Tan SY;Ki S;Ehrlich LI;Poenie M
通讯作者：
Poenie M

Chemokine-Mediated Choreography of Thymocyte Development and Selection.

DOI：
10.1016/j.it.2017.10.007
发表时间：
2018-03
期刊：
Trends in immunology
影响因子：
16.8
作者：
Lancaster JN;Li Y;Ehrlich LIR
通讯作者：
Ehrlich LIR

EBI2 contributes to the induction of thymic central tolerance in mice by promoting rapid motility of medullary thymocytes.

EBI2 通过促进髓质胸腺细胞的快速运动，有助于诱导小鼠胸腺中枢耐受。

DOI：
10.1002/eji.201747020
发表时间：
2017
期刊：
European journal of immunology
影响因子：
5.4
作者：
Ki,Sanghee;Thyagarajan,HiranM;Hu,Zicheng;Lancaster,JessicaN;Ehrlich,LaurenIR
通讯作者：
Ehrlich,LaurenIR

CCR8 is expressed by post-positive selection CD4-lineage thymocytes but is dispensable for central tolerance induction.

CCR8 由阳性选择后 CD4 谱系胸腺细胞表达，但对于中枢耐受诱导来说是可有可无的。

DOI：
10.1371/journal.pone.0200765
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Thyagarajan,HiranM;Lancaster,JessicaN;Lira,SergioA;Ehrlich,LaurenIR
通讯作者：
Ehrlich,LaurenIR

CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment.

DOI：
10.1016/j.celrep.2017.09.016
发表时间：
2017-10-03
期刊：
Cell reports
影响因子：
8.8
作者：
Hu Z;Li Y;Van Nieuwenhuijze A;Selden HJ;Jarrett AM;Sorace AG;Yankeelov TE;Liston A;Ehrlich LIR
通讯作者：
Ehrlich LIR