A spontaneous mutation of the rat Themis gene leads to impaired function of regulatory T cells linked to inflammatory bowel disease.
A spontaneous mutation of the rat Themis gene leads to impaired function of regulatory T cells linked to inflammatory bowel disease.
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大鼠 Themis 基因的自发突变会导致与炎症性肠病相关的调节性 T 细胞功能受损。
DOI：
10.1371/journal.pgen.1002461
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发表时间：
2012-01
期刊：
影响因子：
4.5
通讯作者：
Dejean AS
中科院分区：
文献类型：
--
作者：
Chabod M;Pedros C;Lamouroux L;Colacios C;Bernard I;Lagrange D;Balz-Hara D;Mosnier JF;Laboisse C;Vergnolle N;Andreoletti O;Roth MP;Liblau R;Fournié GJ;Saoudi A;Dejean AS
自发或化学诱导的种系突变可导致孟德尔表型，是发现新基因及其功能的强大工具。在这里，我们报告了一种常染色体隐性突变，该突变在布朗-挪威 (BN) 大鼠群体中自发发生，并被鉴定为导致明显的 T 细胞淋巴细胞减少症。这种突变在一种新的大鼠品系中得到了稳定，该品系被命名为 BNm，意为“BN 突变”。在 BNm 大鼠中，我们发现 T 细胞淋巴细胞减少症起源于胸腺，是 CD4 T 淋巴细胞固有的，并且与炎症性肠病的发生有关。此外，我们证明 BNm 大鼠的外周和胸腺 CD4+ CD25bright 调节性 T 细胞 (Treg) 的抑制活性均存在缺陷。用 BN Treg 补充突变动物可降低疾病发生率和严重程度，因此表明 Treg 功能受损与 BNm 大鼠炎症性肠病的发生有关。此外，BNm 大鼠中效应 CD4 T 细胞的细胞因子谱偏向 Th2 和 Th17 表型。对 BNm×DA 杂交产生的大鼠 CD4 T 细胞淋巴细胞减少症的连锁分析和遗传解剖允许将突变定位在 1 号染色体上，在 1.5 兆碱基间隔内。基因表达和测序研究发现，Themis 基因中插入四个核苷酸会导致移码突变，从而导致其破坏。这一结果首次将 Themis 与 Treg 的抑制功能联系起来，并表明在 Themis 缺陷的动物中，该功能的缺陷与肠道炎症有关。因此，这项研究强调了 Themis 作为新靶基因的重要性，它可以参与以 Treg 区室缺陷导致的慢性炎症为特征的免疫疾病的发病机制。破译人类疾病的遗传基础和了解哺乳动物基因的功能是当今遗传学家面临的主要挑战之一。在这方面，啮齿动物模型是识别新基因和研究与人类疾病有关的基因作用机制的宝贵工具。在这里，我们发现了一种导致大鼠品系血液 CD4 T 淋巴细胞计数减少的自发突变。突变大鼠表现出炎症性肠病的高发病率，这与效应 CD4 T 细胞向 Th2 和 Th17 分泌细胞因子的偏向以及调节性 CD4 T 细胞 (Treg) 的抑制活性受损有关。实验进一步证明了 Treg 的贡献，实验表明，将 Treg 从正常 BN 大鼠转移到突变动物体内可以预防肠道病变的发生。通过淋巴细胞减少症的基因图谱，我们发现了 Themis 基因的破坏。这一结果首次将 Themis 与 Treg 的抑制功能联系起来，并表明在 Themis 缺陷的动物中，这种功能的缺陷容易导致肠道炎症。因此，这种新的大鼠模型强调了 Themis 在调节免疫系统和维持肠道稳态方面的关键作用。
Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BNm for “BN mutated.” In BNm rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4+ CD25bright regulatory T cells (Treg) is defective in BNm rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BNm rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BNm rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BNm×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment. Deciphering the genetic basis of human diseases and understanding the function of mammalian genes are among the main challenges for today's geneticists. In this regard, rodent models represent invaluable tools to identify new genes and to study the mechanisms of action of genes implicated in human diseases. Here, we identified a spontaneous mutation responsible for a reduction of blood CD4 T lymphocyte counts in a rat strain. The mutant rats showed a high incidence of inflammatory bowel disease, which was associated with skewed cytokine secretion by effector CD4 T cells towards Th2 and Th17 and with impairment of the suppressive activity of the regulatory CD4 T cells (Treg). The contribution of Treg was further evidenced by experiments showing that transfer of Treg from normal BN rats to mutant animals prevented the occurrence of bowel lesions. By genetic mapping the lymphopenia, we identified a disruption of the Themis gene. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, a defect of this function predisposes to intestinal inflammation. Thus, this new rat model highlights key roles of Themis both in regulating the immune system and in maintaining intestinal homeostasis.
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影响因子：
4.5
作者：
Festen EA;Goyette P;Green T;Boucher G;Beauchamp C;Trynka G;Dubois PC;Lagacé C;Stokkers PC;Hommes DW;Barisani D;Palmieri O;Annese V;van Heel DA;Weersma RK;Daly MJ;Wijmenga C;Rioux JD
通讯作者：
Rioux JD
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
168.9
作者：
Marks, DJB;Harbord, MWN;Segal, AW
通讯作者：
Segal, AW
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
30.8
作者：
Dubois, Patrick C. A.;Trynka, Gosia;Franke, Lude;Hunt, Karen A.;Romanos, Jihane;Curtotti, Alessandra;Zhernakova, Alexandra;Heap, Graham A. R.;Adany, Roza;Aromaa, Arpo;Bardella, Maria Teresa;van den Berg, Leonard H.;Bockett, Nicholas A.;de la Concha, Emilio G.;Dema, Barbara;Fehrmann, Rudolf S. N.;Fernandez-Arquero, Miguel;Fiatal, Szilvia;Grandone, Elvira;Green, Peter M.;Groen, Harry J. M.;Gwilliam, Rhian;Houwen, Roderick H. J.;Hunt, Sarah E.;Kaukinen, Katri;Kelleher, Dermot;Korponay-Szabo, Ilma;Kurppa, Kalle;MacMathuna, Padraic;Maki, Markku;Mazzilli, Maria Cristina;McCann, Owen T.;Mearin, M. Luisa;Mein, Charles A.;Mirza, Muddassar M.;Mistry, Vanisha;Mora, Barbara;Morley, Katherine I.;Mulder, Chris J.;Murray, Joseph A.;Nunez, Concepcion;Oosterom, Elvira;Ophoff, Roel A.;Polanco, Isabel;Peltonen, Leena;Platteel, Mathieu;Rybak, Anna;Salomaa, Veikko;Schweizer, Joachim J.;Sperandeo, Maria Pia;Tack, Greetje J.;Turner, Graham;Veldink, Jan H.;Verbeek, Wieke H. M.;Weersma, Rinse K.;Wolters, Victorien M.;Urcelay, Elena;Cukrowska, Bozena;Greco, Luigi;Neuhausen, Susan L.;McManus, Ross;Barisani, Donatella;Deloukas, Panos;Barrett, Jeffrey C.;Saavalainen, Paivi;Wijmenga, Cisca;van Heel, David A.
通讯作者：
van Heel, David A.