ABSTRACT

Increased T-regulatory cell activity drives tumor progression in the compound APC^min/+/enterotoxic Bacteroides fragilis colon cancer model. At the same time, how microbially-induced inflammation promotes T-regulatory cell expansion in the dysplastic intestine remains poorly described. Analysis of post-infection immune cell kinetics in the colon lamina propria revealed that CD4+ Foxp3+ cell numbers increased by 25-fold between days 3–14. Importantly, T-regulatory cell expansion was preceded by a 12-fold spike in lamina propria CD11b⁺ cell numbers between days 0–4; suggesting a link between the myeloid compartment and the T-regulatory cells. Consistent with this notion, in vitro co-culture studies utilizing sorted myeloid cell subsets and CD4⁺ T-cells demonstrated that the CD11b⁺CX3CR1⁺ but not the CD11b⁺CX3CR1⁻ subset preferentially induced Foxp3 expression in CD4⁺ T-cells. Phenotypic analysis revealed that the CD11b⁺CX3CR1⁺ subset represented a homogenous CD64⁺CD24⁻CD103a⁻ macrophage population. Global CX3CR1 knockout or conditional depletion of CX3CR1⁺ myeloid cells resulted in diminished CD4⁺Foxp3⁺ cell expansion and a 3 to 6-fold reduction in tumor burden establishing CX3CR1⁺ macrophages as a major driver of the T-regulatory cell-tumor axis. Quantitative analysis of CD11b⁺ myeloid cell subsets for IFNβ mRNA revealed that the CX3CR1⁺ macrophages expressed 15-fold higher levels of IFNβ in comparison to the CX3CR1⁻ myeloid subset. Antibody mediated neutralization of IFNβ resulted in the suppression of CD4⁺Foxp3⁺ cell induction and tumor growth, demonstrating the central role of IFNβ in mediating CX3CR1⁺ macrophage-driven T-regulatory cell expansion. These studies shed new mechanistic light on the cellular ontogeny of pro-tumorigenic T-regulatory cells in the inflamed colon of the APC^min/+ mouse.

抽象的

在化合物APC ^{min / +} /肠溶性脆弱拟杆菌（Bacteroides fragilis）结肠癌模型中，增加的T调节细胞活性可驱动肿瘤进展。同时，关于微生物诱导的炎症如何促进发育不良的肠道中T调节细胞的扩增的描述仍然很少。对结肠固有层感染后免疫细胞动力学的分析表明，CD4 + Foxp3 +细胞数量在3-14天之间增加了25倍。重要的是，在T调节性细胞扩增之前，固有固有层CD11b ⁺细胞数量在0至4天之间增加了12倍。提示髓样区室与T调节细胞之间存在联系。与此概念一致，在体外利用排序髓样细胞亚群和CD4的共培养研究⁺ T细胞证明了细胞CD11b ⁺ CX3CR1 ⁺但不是细胞CD11b ⁺ CX3CR1 ^-子集优先诱导CD4 Foxp3表达⁺ T细胞。表型分析表明，该细胞CD11b ⁺ CX3CR1 ⁺子集表示的均匀的CD64 ⁺ CD24 ^- CD103a ^-巨噬细胞群。整体CX3CR1敲除或CX3CR1 ⁺骨髓细胞的条件耗竭导致CD4 ⁺ Foxp3 ⁺减少CX3CR1 ⁺巨噬细胞成为T调节细胞肿瘤轴的主要驱动力，细胞膨胀和肿瘤负担减少3至6倍。的CD11b的定量分析⁺髓样细胞亚群为IFNβ的mRNA，发现该CX3CR1 ⁺巨噬细胞表达相比于CX3CR1 15倍高的水平IFNβ的^-髓样子集。抗体介导的IFNβ的中和导致CD4 ⁺ Foxp3 ⁺细胞诱导和肿瘤生长的抑制，证明IFNβ在介导CX3CR1 ^+中的核心作用巨噬细胞驱动的T调节细胞扩增。这些研究为APC ^{min / +}小鼠发炎结肠中促肿瘤T调节细胞的细胞发育提供了新的机制。