权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

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。