Golec Dominic P, Hoeppli Romy E, Henao Caviedes Laura M, McCann Jillian, Levings Megan K, Baldwin Troy A
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.
Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
J Exp Med. 2017 Aug 7;214(8):2421-2435. doi: 10.1084/jem.20170844. Epub 2017 Jun 26.
Strong T cell receptor (TCR) signaling largely induces cell death during thymocyte development, whereas weak TCR signals induce positive selection. However, some T cell lineages require strong TCR signals for differentiation through a process termed agonist selection. The signaling relationships that underlie these three fates are unknown. RasGRP1 is a Ras activator required to transmit weak TCR signals leading to positive selection. Here, we report that, despite being dispensable for thymocyte clonal deletion, RasGRP1 is critical for agonist selection of TCRαβCD8αα intraepithelial lymphocyte (IEL) progenitors (IELps), even though both outcomes require strong TCR signaling. Bim deficiency rescued IELp development in RasGRP1 mice, suggesting that RasGRP1 functions to promote survival during IELp generation. Additionally, expression of CD122 and the adhesion molecules αβ and CD103 define distinct IELp subsets with differing abilities to generate TCRαβCD8αα IEL in vivo. These findings demonstrate that RasGRP1-dependent signaling underpins thymic selection processes induced by both weak and strong TCR signals and is differentially required for fate decisions derived from a strong TCR stimulus.
在胸腺细胞发育过程中，强烈的T细胞受体（TCR）信号大多会诱导细胞死亡，而微弱的TCR信号则会诱导阳性选择。然而，一些T细胞谱系需要通过一个称为激动剂选择的过程，依靠强烈的TCR信号来实现分化。这三种命运背后的信号传导关系尚不清楚。RasGRP1是一种Ras激活剂，它是传递导致阳性选择的微弱TCR信号所必需的。在此，我们报告，尽管RasGRP1对于胸腺细胞克隆性缺失并非必需，但它对于TCRαβCD8αα上皮内淋巴细胞（IEL）祖细胞（IELp）的激动剂选择至关重要，尽管这两种结果都需要强烈的TCR信号。Bim缺陷挽救了RasGRP1基因敲除小鼠中IELp的发育，这表明RasGRP1在IELp生成过程中发挥促进存活的作用。此外，CD122以及黏附分子αβ和CD103的表达定义了不同的IELp亚群，它们在体内生成TCRαβCD8αα IEL的能力各不相同。这些发现表明，RasGRP1依赖的信号传导是由微弱和强烈的TCR信号诱导的胸腺选择过程的基础，并且对于源自强烈TCR刺激的命运决定有不同的需求。
