CD45Rb-low effector T cells require IL-4 to induce IL-10 in FoxP3 Tregs and to protect mice from inflammation

CD4+ effector/memory T cells (Tem) represent a leading edge of the adaptive immune system responsible for protecting the body from infection, cancer, and other damaging processes. However, a subset of Tem cells with low expression of CD45Rb (RbLoTem) has been shown to suppress inflammation despite their effector surface phenotype and the lack of FoxP3 expression, the canonical transcription factor found in most regulatory T cells. In this report, we show that RbLoTem cells can suppress inflammation by influencing Treg behavior. Co-culturing activated RbLoTem and Tregs induced high expression of IL-10 in vitro, and conditioned media from RbLoTem cells induced IL-10 expression in FoxP3+ Tregs in vitro and in vivo, indicating that RbLoTem cells communicate with Tregs in a cell-contact independent fashion. Transcriptomic and multi-analyte Luminex data identified both IL-2 and IL-4 as potential mediators of RbLoTem-Treg communication, and antibody-mediated neutralization of either IL-4 or CD124 (IL-4Rα) prevented IL-10 induction in Tregs. Moreover, isolated Tregs cultured with recombinant IL-2 and IL-4 strongly induced IL-10 production. Using house dust mite (HDM)-induced airway inflammation as a model, we confirmed that the in vivo suppressive activity of RbLoTem cells was lost in IL-4-ablated RbLoTem cells. These data support a model in which RbLoTem cells communicate with Tregs using a combination of IL-2 and IL-4 to induce robust expression of IL-10 and suppression of inflammation.

CD4+效应记忆T细胞（CD4+ effector/memory T cells，Tem）是适应性免疫系统的前沿效应亚群，负责保护机体抵御感染、肿瘤及其他损伤性病理过程。
然而，一类低表达CD45Rb的Tem细胞亚群（RbLoTem）尽管具备效应性细胞表面表型，且不表达多数调节性T细胞（regulatory T cells，Tregs）中标志性的转录因子FoxP3，却被证实具有抗炎活性。
本研究证实，RbLoTem细胞可通过调控调节性T细胞的行为发挥抗炎作用。体外共培养活化的RbLoTem细胞与Tregs可诱导白细胞介素10（IL-10）高表达；RbLoTem细胞的条件培养基可在体内外诱导FoxP3+ Tregs表达IL-10，表明该细胞群可通过不依赖细胞接触的方式与Tregs进行细胞间通讯。
转录组学分析与多因子Luminex检测数据显示，白细胞介素2（IL-2）与白细胞介素4（IL-4）均为RbLoTem与Tregs之间通讯的潜在介质；且通过抗体介导中和IL-4或CD124（IL-4Rα），可阻断Tregs中IL-10的诱导表达。
此外，将分离纯化的Tregs与重组IL-2、IL-4共同培养，可显著促进IL-10的产生。
本研究以屋尘螨（house dust mite，HDM）诱导的气道炎症为模型，证实IL-4基因敲除的RbLoTem细胞丧失了体内抗炎活性。
上述数据支持如下模型：RbLoTem细胞可通过联合分泌IL-2与IL-4与Tregs进行通讯，诱导Tregs高水平表达IL-10，从而实现炎症抑制。