CARMA1 is necessary for optimal T cell responses in a murine model of allergic asthma.
CARMA1 is necessary for optimal T cell responses in a murine model of allergic asthma.
复制标题
CARMA1对于在过敏性哮喘的鼠模型中最佳T细胞反应是必需的。
DOI：
10.4049/jimmunol.1101348
复制
发表时间：
2011-12-15
期刊：
影响因子：
--
通讯作者：
Medoff BD
中科院分区：
文献类型：
--
作者：
Ramadas RA;Roche MI;Moon JJ;Ludwig T;Xavier RJ;Medoff BD
CARMA 1是T细胞活化所必需的淋巴细胞特异性支架蛋白。CARMA 1的缺失可防止哮喘小鼠模型中由于幼稚T细胞活化缺陷而发生过敏性气道炎症。然而，目前尚不清楚CARMA 1是否对炎症最初建立后的效应和记忆T细胞应答很重要，这一发现与靶向CARMA 1的哮喘治疗更相关。在目前的研究中，我们试图阐明CARMA 1在先前已被激活的T细胞中的作用。我们使用了通过OX 40驱动的Cre重组酶（OX 40 +/CreCARMA 1 F/F）可以选择性删除T细胞中floxed CARMA 1外显子的小鼠，我们报告了来自这些小鼠的CD 4 + T细胞在体外具有受损的T细胞再活化应答和NF-κB信号传导。此外，在依赖于记忆T细胞功能的过敏性气道炎症的体内回忆模型中，OX 40 +/CreCARMA 1F/F小鼠具有减弱的嗜酸性气道炎症、T细胞活化和Th 2细胞因子产生。使用MHC II类四聚体，我们证明了抗原特异性记忆T细胞的发育和维持在OX 40 +/CreCARMA 1F/F小鼠中不受影响。此外，Th 2极化的OX 40 +/CreCARMA 1F/F抗原特异性CD 4 + T细胞过继转移到野生型小鼠中诱导的气道炎症对抗原攻击的应答显著低于野生型Th 2细胞的转移。这些数据证明了CARMA 1在效应和记忆T细胞应答中的新作用，并表明靶向CARMA 1的治疗策略可以帮助治疗慢性炎症性疾病，如哮喘。
CARMA1 is a lymphocyte-specific scaffold protein necessary for T cell activation. Deletion of CARMA1 prevents the development of allergic airway inflammation in a mouse model of asthma due to a defect in naïve T cell activation. However, it is unknown if CARMA1 is important for effector and memory T cell responses after the initial establishment of inflammation, findings which would be more relevant to asthma therapies targeted to CARMA1. In the current study, we sought to elucidate the role of CARMA1 in T cells that have been previously activated. Using mice in which floxed CARMA1 exons can be selectively deleted in T cells by OX40 driven Cre recombinase (OX40+/CreCARMA1F/F), we report that CD4+ T cells from these mice have impaired T cell reactivation responses and NF-κB signaling in vitro. Furthermore, in an in vivo recall model of allergic airway inflammation that is dependent on memory T cell function, OX40+/CreCARMA1F/F mice have attenuated eosinophilic airway inflammation, T cell activation and Th2 cytokine production. Using MHC class II tetramers, we demonstrate that the development and maintenance of antigen-specific memory T cells is not affected in OX40+/CreCARMA1F/F mice. In addition, adoptive transfer of Th2-polarized OX40+/CreCARMA1F/F antigen-specific CD4+ T cells into wild-type mice induces markedly less airway inflammation in response to antigen challenge than transfer of wild-type Th2 cells. These data demonstrate a novel role for CARMA1 in effector and memory T cell responses and suggests that therapeutic strategies targeting CARMA1 could help treat chronic inflammatory disorders such as asthma.
登录
查看更多内容
影响因子：
30.5
作者：
Gaide, O;Favier, B;Thome, M
通讯作者：
Thome, M
影响因子：
5.4
作者：
Kalia, Vandana;Sarkar, Surojit;Ahmed, Rafi
通讯作者：
Ahmed, Rafi
影响因子：
3.5
作者：
Gaide, O;Martinon, F;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
9.8
作者：
Barnes MJ;Krebs P;Harris N;Eidenschenk C;Gonzalez-Quintial R;Arnold CN;Crozat K;Sovath S;Moresco EM;Theofilopoulos AN;Beutler B;Hoebe K
通讯作者：
Hoebe K
DOI：
10.4049/jimmunol.0902185
发表时间：
2010-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Finkelman FD;Hogan SP;Hershey GK;Rothenberg ME;Wills-Karp M
通讯作者：
Wills-Karp M