Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI.
Blood Research Institute, Versiti, Milwaukee, WI; and.
Blood Adv. 2022 May 10;6(9):2791-2804. doi: 10.1182/bloodadvances.2021006084.
Gastrointestinal (GI) tract involvement is a major determinant for subsequent morbidity and mortality arising during graft-versus-host disease (GVHD). CD4+ T cells that produce granulocyte-macrophage colony stimulating factor (GM-CSF) have emerged as central mediators of inflammation in this tissue site as GM-CSF serves as a critical cytokine link between the adaptive and innate arms of the immune system. However, cellular heterogeneity within the CD4+ GM-CSF+ T-cell population due to the concurrent production of other inflammatory cytokines has raised questions as to whether these cells have a common ontology or if a unique CD4+ GM-CSF+ subset exists that differs from other defined T helper subtypes. Using single-cell RNA sequencing analysis (scRNAseq), we identified two CD4+ GM-CSF+ T-cell populations that arose during GVHD and were distinguishable according to the presence or absence of interferon-γ (IFN-γ) coexpression. CD4+ GM-CSF+ IFN-γ- T cells, which emerged preferentially in the colon, had a distinct transcriptional profile, used unique gene regulatory networks, and possessed a nonoverlapping T-cell receptor repertoire compared with CD4+ GM-CSF+ IFN-γ+ T cells as well as all other transcriptionally defined CD4+ T-cell populations in the colon. Functionally, this CD4+ GM-CSF+ T-cell population contributed to pathologic damage in the GI tract that was critically dependent on signaling through the interleukin-17 (IL-7) receptor but was independent of type 1 interferon signaling. Thus, these studies help to unravel heterogeneity within CD4+ GM-CSF+ T cells that arise during GVHD and define a developmentally distinct colitogenic T helper subtype GM-CSF+ subset that mediates immunopathology.
胃肠道（GI）道受累是移植物抗宿主病（GVHD）期间随后发生发病率和死亡率的主要决定因素。产生粒细胞-巨噬细胞集落刺激因子（GM-CSF）的 CD4+T 细胞已成为该组织部位炎症的主要介质，因为 GM-CSF 是免疫系统适应性和固有免疫之间的关键细胞因子联系。然而，由于同时产生其他炎症细胞因子，CD4+GM-CSF+T 细胞群体中的细胞异质性引发了一个问题，即这些细胞是否具有共同的本体论，或者是否存在一个不同于其他定义的辅助性 T 细胞亚型的独特的 CD4+GM-CSF+亚群。使用单细胞 RNA 测序分析（scRNAseq），我们鉴定了在 GVHD 期间出现的两种 CD4+GM-CSF+T 细胞群体，并且可以根据干扰素-γ（IFN-γ）共表达的存在与否来区分。CD4+GM-CSF+IFN-γ-T 细胞优先在结肠中出现，具有独特的转录谱，使用独特的基因调控网络，并且与 CD4+GM-CSF+IFN-γ+T 细胞以及结肠中所有其他转录定义的 CD4+T 细胞群体相比具有非重叠的 T 细胞受体库。在功能上，该 CD4+GM-CSF+T 细胞群体有助于 GI 道的病理性损伤，这严重依赖于白细胞介素-17（IL-17）受体的信号传导，但独立于 1 型干扰素信号传导。因此，这些研究有助于揭示 GVHD 期间出现的 CD4+GM-CSF+T 细胞中的异质性，并定义了一种发育上不同的致结肠炎辅助性 T 细胞亚群 GM-CSF+亚群，该亚群介导免疫病理学。
