A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFß
A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFß
复制标题
CD4 效应记忆 T 细胞的一个子集限制对肺部病毒感染的免疫力，并通过激活潜在的 TGFα 来预防组织病理学
DOI：
10.1101/2023.03.02.527395
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
McEntee C
中科院分区：
文献类型：
--
作者：
McEntee C
对病原体再次暴露的快速免疫反应支持免疫记忆，对不同病原体（如异源或新型病毒株）的保护需要交叉反应记忆T细胞。因此，了解控制记忆T细胞功能的途径对于合理设计病毒疫苗非常重要，并将有助于发现增强抗病毒免疫的治疗方法。在这里，我们确定了一个记忆T细胞亚群，它限制了对病毒再感染的二次免疫反应，这对于防止宿主组织损伤至关重要。我们发现CD4+效应记忆T （TEM）细胞群通过表达整合素αvβ8激活重要的免疫调节细胞因子TGFβ。整合素αvβ8的表达标志着CD4+TEM中转录不同的亚群，富含抗炎途径。小鼠CD4+TEM上整合素αvβ8的缺失，而Foxp3+调节性T细胞（TREG）上的缺失，导致继发性甲型流感病毒（IAV）感染后病毒特异性CD8+T细胞反应加剧，这与病毒清除能力增强有关。然而，在继发性IAV感染后，尽管加速了清除，但整合素αvβ8在CD4+ tem8细胞上表达的缺失导致肺部病理增强，而αvβ8+CD4+ tem细胞的过继转移完全逆转了这一过程。这些数据强调了一种新的途径，通过这种途径，一种独特的CD4+记忆T细胞亚群抑制抗病毒免疫，以防止继发性病毒感染期间宿主组织损伤。这些途径可以靶向治疗，要么增强记忆t细胞介导的免疫，要么在病毒感染期间抑制宿主组织损伤。
A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+effector memory T (TEM) cells activate the important immunoregulatory cytokine TGFβ, via expression of an integrin, αvβ8. Integrin αvβ8 expression marks a transcriptionally distinct sub-population of CD4+TEM, enriched for anti-inflammatory pathways. Loss of integrin αvβ8 on murine CD4+TEM, but not Foxp3+regulatory T cells (TREG), led to exacerbated virus-specific CD8+T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin αvβ8 expression on CD4+TEMresulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of αvβ8+CD4+TEMcells. These data highlight a new pathway by which a distinct CD4+memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.