Chemokine System in DC and Lymphocyte Function

DC 和淋巴细胞功能中的趋化因子系统

• 批准号: 6891558
• 负责人: SEEMA Singh AHUJA
• 金额: $ 31.18万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891558
• 关键词: B lymphocyte; antigen presentation; cell differentiation; cell migration; chemokine; chemokine receptor; chemotaxis; dendritic cells; helper T lymphocyte; laboratory mouse; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): Dendritic cells (DC)/Langerhans cells (LC; skin DCs) are sentinels of the immune system. There is growing evidence to suggest that chemokines and their receptors are important determinants of DC/LC trafficking, and that these molecules also play a significant role in T-cell and B-cell function. Over the last two years, significant attention has been focused on CC chemokine receptor 6 (CCR6), CCR7, and CXCR5 and their ligands in DC, and T- and B-cell function, and lymphoid organ homeostasis. However, there is a paucity of information regarding the in vivo role of other chemokine receptors/ligands in these processes. To test the hypothesis that the chemokine system plays an important role in LC/DC and T- and B-cell functions in vivo, we have taken the approach of investigating the loss or gain of immune function in mice lacking one or more of these molecules. In preliminary studies, we found that deficiency of CCR2 but not CCR5 led to distinct defects in DC biology. LC migration to the draining lymph nodes in CCR2-null mice was markedly impaired. CCR2-null mice had lower numbers of DCs in the spleen and this was primarily due to a reduction in the CD8alpha+ Thi-inducing subset of DCs. Additionally, there was a block in the Leishmania major infection-induced relocalization of splenic DCs from the marginal zone to the T-cell areas. We propose that these DC defects in conjunction with increased expression of BLC, a B-cell-specific chemokine, may collectively contribute to the striking B-cell outgrowth and Th2 cytokine-biased nonhealing phenotype that we observed in CCR2-deficient mice infected with L. major. We also found evidence for increased apoptotic activity in the lymphatic channels and infected lymph nodes of CCR2-null but not CCR5-null mice. To test our hypothesis, and to investigate the mechanisms underlying the phenotypes observed in the chemokine receptor gene-deleted mice, we propose four specific aims We will determine the mechanism(s) by which CCR2 influences (1) LC/DC migration, localization and function; (2) APC-effector cell interactions in lymphoid organs; (3) the localization and function of Th1/Th2 inducing DC subsets in the spleen; and (4) we will determine if expression of CCR2 and CCR5 influence Thl and Th2 lymphocyte cell differentiation and homing. These studies will further significantly our understanding of the role of the chemokine system in regulating LC/DC and lymphocyte function, and these insights will offer new opportunities/targets for therapeutic intervention to suppress (transplantation) or stimulate (cancer) the immune response.

描述（申请人提供）：树突状细胞（DC）/朗格汉斯细胞（LC； 皮肤 DC）是免疫系统的哨兵。越来越多的证据表明 表明趋化因子及其受体是 DC/LC 的重要决定因素 贩运，并且这些分子也在 T 细胞中发挥重要作用 和 B 细胞功能。近两年来，备受关注 专注于 CC 趋化因子受体 6 (CCR6)、CCR7 和 CXCR5 及其配体 DC、T 细胞和 B 细胞功能以及淋巴器官稳态。然而，有 关于其他趋化因子体内作用的信息很少 这些过程中的受体/配体。检验趋化因子的假设 系统在体内 LC/DC 以及 T 细胞和 B 细胞功能中发挥着重要作用，我们 采取了研究免疫功能丧失或增强的方法 缺乏一种或多种这些分子的小鼠。在初步研究中，我们发现 CCR2 的缺陷而非 CCR5 的缺陷导致了 DC 生物学的明显缺陷。液相色谱 CCR2缺失小鼠向引流淋巴结的迁移明显受损。 CCR2 缺失小鼠的脾脏中 DC 数量较少，这主要是 由于 CD8α+ Thi 诱导 DC 子集的减少。此外， 利什曼原虫主要感染引起的重新定位受到阻碍 脾 DC 从边缘区到 T 细胞区域。我们建议这些 DC 缺陷与 BLC（一种 B 细胞特异性）表达增加相关 趋化因子，可能共同促进 B 细胞和 Th2 细胞的惊人生长 我们在 CCR2 缺陷小鼠中观察到的细胞因子偏向的不愈合表型 感染了 L. Major。我们还发现了细胞凋亡活性增加的证据 存在于 CCR2 缺失的淋巴管和感染淋巴结中，但不存在 CCR5 缺失小鼠。检验我们的假设并研究其机制 在趋化因子受体基因缺失的小鼠中观察到的表型的基础， 我们提出四个具体目标 我们将确定 CCR2 的机制 影响（1）LC/DC迁移、定位和功能； (2) APC效应器 淋巴器官中的细胞相互作用； （三）定位与功能 Th1/Th2 在脾脏中诱导 DC 亚群； (4) 我们将确定是否 CCR2和CCR5表达影响Thl和Th2淋巴细胞 分化和归巢。这些研究将进一步显着我们的 了解趋化因子系统在调节 LC/DC 中的作用和 淋巴细胞功能，这些见解将提供新的机会/目标 用于抑制（移植）或刺激的治疗干预 （癌症）免疫反应。

项目成果

Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis.

CC趋化因子受体2缺失小鼠的实验性关节炎与严重的人类类风湿性关节炎非常相似。

• DOI: 10.1172/jci20126
• 发表时间: 2004
• 期刊: The Journal of clinical investigation
• 作者: Quinones,MarlonP;Ahuja,SunilK;Jimenez,Fabio;Schaefer,Jason;Garavito,Edgar;Rao,Arun;Chenaux,George;Reddick,RobertL;Kuziel,WilliamA;Ahuja,SeemaS
• 通讯作者: Ahuja,SeemaS

CC chemokine receptor (CCR)-2 prevents arthritis development following infection by Mycobacterium avium.

CC 趋化因子受体 (CCR)-2 可预防鸟分枝杆菌感染后关节炎的发展。

• DOI: 10.1007/s00109-006-0039-3
• 发表时间: 2006
• 期刊: Journal of molecular medicine (Berlin, Germany)
• 作者: Quinones,MarlonP;Jimenez,Fabio;Martinez,Hernan;Estrada,CarlosA;Willmon,Opal;Dudley,Molly;Kuziel,WilliamA;Melby,PeterC;Reddick,RobertL;Ahuja,SunilK;Ahuja,SeemaS
• 通讯作者: Ahuja,SeemaS

CCR2 plays a critical role in dendritic cell maturation: possible role of CCL2 and NF-kappa B.

• DOI: 10.4049/jimmunol.0803494
• 发表时间: 2010-05-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Jimenez F;Quinones MP;Martinez HG;Estrada CA;Clark K;Garavito E;Ibarra J;Melby PC;Ahuja SS
• 通讯作者: Ahuja SS

CD8α⁺ dendritic cells improve collagen-induced arthritis in CC chemokine receptor (CCR)-2 deficient mice.

• DOI: 10.1016/j.imbio.2011.03.012
• 发表时间: 2011-09
• 期刊: IMMUNOBIOLOGY
• 影响因子: 2.8
• 作者: Ibarra, Jessica M.;Quinones, Marlon P.;Estrada, Carlos A.;Jimenez, Fabio;Martinez, Hernan G.;Ahuja, Seema S.
• 通讯作者: Ahuja, Seema S.

CC chemokine receptor 5 influences late-stage atherosclerosis.

• DOI: 10.1016/j.atherosclerosis.2007.03.026
• 发表时间: 2007-11-01
• 期刊: Atherosclerosis
• 影响因子: 5.3
• 作者: Quinones, Marlon P;Martinez, Hernan G;Ahuja, Seema S
• 通讯作者: Ahuja, Seema S