Mucosal Chemokines and CD8+ T Cell Immunity to Genital Herpes

粘膜趋化因子和 CD8 T 细胞对生殖器疱疹的免疫

基本信息

批准号：
10450154
负责人：
Lbachir BenMohamed
金额：
$ 59.97万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450154
关键词：
Antigens Basic Science Biology Bone Marrow CCL25 gene CD8-Positive T-Lymphocytes CD8B1 gene CXC chemokine receptor 3 CXCL10 gene CXCL14 gene CXCL9 gene CXCR3 gene Cells Chemotactic Factors Data Development Disease Epithelial Cells Exposure to Female genitalia GPR2 gene Generations Goals Herpesviridae Infections Homeostasis Homing Human Herpesvirus 2 Immunity Immunologic Surveillance Immunotherapy Infection Inflammation Mediators Intravaginal Administration Investigation Kinetics Knowledge Longevity Lymphocyte Maintenance Mediating Mediator of activation protein Memory Modeling Molecular Mucosal Immunity Mucous Membrane Mus Peripheral Play Process Production Publishing Research Project Grants Role Simplexvirus Source T memory cell T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Testing Tissues Translational Research Vaccines Vagina Viral Viral Antigens base chemokine chemokine receptor genital herpes mouse model novel novel vaccines pathogen pathogenic virus receptor recruit reproductive tract vaccine strategy vaginal mucosa

项目摘要

PROJECT SUMMARY/ABSTRACT Mucosal tissues are frontline barriers that are continuously exposed to infectious pathogens. Developing and maintaining protective mucosal tissue-resident memory T cells (TRM cells) is necessary for immune surveillance. However, the mechanisms controlling homing and maintenance of mucosal TRM cells are unknown and likely distinct from those regulating conventional circulating effector memory (TEM) and central memory (TCM) cells. A currently accepted paradigm is that mucosal chemokines (i.e., CCL25, CCL28, CXCL14, and CXCL17) play a crucial role in mobilizing TRM cells in mucosal tissues, and may occur independent of local antigen recognition. However, several major gaps remain, including: (1) the identity of the mucosal chemokines involved; (2) their cellular source; and (3) the cellular and molecular mechanisms through which they regulate mobilization of anti- viral mucosal CD8+ TRM cells. This proposal uses herpes simplex virus type 2 (HSV-2) as a model viral pathogen to elucidate the underlying mechanisms that regulate mobilization of HSV-specific CD8+ TRM cells in the vaginal mucosal tissue. Our published and preliminary data indicate that: (A) Elevated numbers of HSV-specific memory CD62LlowCCR7lowCD103highCD8+ TRM cells and CXCR8+CD8+ T cells are present in the vaginal mucosa of HSV- 2 infected asymptomatic mice as compared to symptomatic mice; (B) Mucosal chemokines CXCL17 and CCL28 are highly expressed in the vaginal mucosal tissues of HSV-2-infected asymptomatic mice, with no apparent genital herpes disease; (C) CD8+ TRM cells that reside in vaginal mucosa of asymptomatic mice express CXCR3 (the receptor for T cell-attracting chemokines CXCL9 and CXCL10),CXCR8, and CCR10 (the receptors for CXCL17 and CCL28, respectively); (D) Intravaginal administration of T cell-attracting chemokines CXCL9 and CXCL10 is associated with increased recruitment of CXCR8+CD8+, CCR10+CD8+ TRM cells to the vaginal mucosa of asymptomatic mice; and (E) Exogenous CXCL9 and CXCL10 significantly increased expression of CXCR3, CXCR8, and CCR10 receptors on vaginal mucosa-resident CD8+ TRM cells. Based on these findings, we hypothesize that CXCL17 and CCL28 play a crucial role in homing and maintenance of vaginal mucosal tissue- resident CD8+ TRM cells, which protect from genital herpes. Our Specific Aims include: Aim 1 will identify the cellular sources of CXCL17 and CCL28 in vaginal mucosa and the mediators that regulate their expression. Aim 2 will investigate the role of CXCL17 and CCL28 mucosal chemokines and study the need for local viral antigen expression in developing, maintaining, and expanding CD8+ TRM cells within the vaginal mucosa. Aim 3 will develop a novel “prime, pull, and keep” vaccine strategy to increase the size and maintenance of vaginal mucosa- resident CD8+ TRM cells to protect against genital herpes. This is based on three sequential steps of intravaginal administration of: (1) CD8+ T cell epitopes (prime); (2) CXCL9 and/or CXCL10 T-cell attracting chemokines (pull); and (3) CXCL17 and/or CCL28 mucosal chemokines (keep). Successful completion of this basic and translational research project will pave the way towards the development of an effective mucosal herpes vaccine.

项目概要/摘要粘膜组织是不断暴露于感染性病原体的前线屏障。维持保护性粘膜组织驻留记忆 T 细胞（TRM 细胞）对于免疫监视是必要的。然而，控制粘膜 TRM 细胞归巢和维持的机制尚不清楚，并且很可能与调节传统循环效应记忆（TEM）和中央记忆（TCM）细胞的细胞不同。目前公认的范例是粘膜趋化因子（即 CCL25、CCL28、CXCL14 和 CXCL17）发挥着 TRM 细胞在粘膜组织中的动员中发挥着至关重要的作用，并且可能独立于局部抗原识别而发生。然而，仍然存在一些主要空白，包括：（1）所涉及的粘膜趋化因子的身份；（2）它们的特性；细胞来源；和（3）它们调节抗-动员的细胞和分子机制。病毒粘膜 CD8+ TRM 细胞该提案使用 2 型单纯疱疹病毒 (HSV-2) 作为模型病毒病原体。阐明调节 HSV 特异性 CD8+ TRM 细胞在阴道动员的潜在机制我们发表的初步数据表明： (A) HSV 特异性记忆数量增加。 CD62LlowCCR7lowCD103highCD8+ TRM细胞和CXCR8+CD8+ T细胞存在于HSV-的阴道粘膜中 2 只受感染的无症状小鼠与有症状小鼠相比 (B) 粘膜趋化因子 CXCL17 和 CCL28；在HSV-2感染的无症状小鼠的阴道粘膜组织中高表达，且无明显变化。生殖器疱疹疾病；(C) 无症状小鼠阴道粘膜中的 CD8+ TRM 细胞表达 CXCR3 （T 细胞吸引趋化因子 CXCL9 和 CXCL10 的受体）、CXCR8 和 CCR10（T 细胞趋化因子 CXCL9 和 CXCL10 的受体） (D) 阴道内施用 T 细胞吸引趋化因子 CXCL9 和 CXCL10 与 CXCR8+CD8+、CCR10+CD8+ TRM 细胞向阴道粘膜的募集增加相关无症状小鼠；和（E）外源CXCL9和CXCL10显着增加CXCR3的表达，基于这些发现，我们研究了阴道粘膜驻留 CD8+ TRM 细胞上的 CXCR8 和 CCR10 受体。 CXCL17和CCL28在阴道粘膜组织的归巢和维持中发挥着至关重要的作用- 常驻 CD8+ TRM 细胞，可预防生殖器疱疹。我们的具体目标包括：目标 1 将确定感染者。阴道粘膜中 CXCL17 和 CCL28 的细胞来源以及调节其表达的介质。 2.将调查CXCL17和CCL28粘膜趋化因子的作用并研究局部病毒抗原的需要目标 3 将在阴道粘膜内发育、维持和扩增 CD8+ TRM 细胞中表达。开发一种新颖的“引发、拉动和保留”疫苗策略，以增加阴道粘膜的大小和维持常驻 CD8+ TRM 细胞可预防生殖器疱疹这是基于阴道内的三个连续步骤。施用：（1）CD8+T细胞表位（引发）；（2）CXCL9和/或CXCL10 T细胞吸引趋化因子（拉）； (3)CXCL17和/或CCL28粘膜趋化因子（保留）成功完成此基本和。转化研究项目将为开发有效的粘膜疱疹疫苗铺平道路。