Effect of allergic asthma on CD8+ TRM-mediated protection from infection

患有局部Th 2型炎性疾病（包括过敏性哮喘）的个体 严重的病毒感染，但原因尚不清楚。防御局部感染依赖于组织 驻留记忆CD 8 + T细胞（TRM），驻留在外周组织内，并提供快速防御， 病原体和肿瘤。抗原攻击后，CD 8 + TRM分泌激活先天细胞的细胞因子， 诱导抗病毒和抗细菌基因表达，并募集循环白细胞用于病原体控制。 考虑到它们在宿主保护中的核心作用，我们假设CD 8 + TRM的损伤有助于严重的 特应性疾病患者的感染。我们的初步数据表明，IL-4独特地防止TGF-β 1， 诱导粘附受体CD 49 a和CD 103的表达，这是CD 8 + TRM持久性所需的 在外周组织中。与此同时，体内研究表明，CD 8 + T细胞暴露于IL-4会降低CD 8 + T细胞和IL-4的表达。 它们的CD 103表达以及它们在皮肤内的积累。根据这些初步数据，我们 我建议使用过敏性哮喘小鼠模型来扩展这些研究，以检验Th 2 细胞因子损害肺CD 8 + TRM形成、持久性和对呼吸道感染的防御。具体地说， 我们建议：1）确定Th 2型微环境对肺CD 8 + TRM的影响 2）确定CD 8 + TRM的表型稳定性;以及 IL-4对肺CD 8 + TRM介导的针对流感感染的保护性免疫的影响。

Individuals suffering from local Th2-type inflammatory diseases, including allergic asthma have increased risk for serious viral infections, but the cause is unclear. Defense against local infections relies on tissue resident memory CD8+ T cells (TRM) that reside within peripheral tissues and deliver rapid defense against pathogens and tumors. Following antigen challenge, CD8+ TRM secrete cytokines that activate innate cells, induce expression of anti-viral and anti-bacterial genes, and recruit circulating leukocytes for pathogen control. Given their central role in host protection, we hypothesize that impairment of CD8+ TRM contributes to severe infection in patients with atopic diseases. Our preliminary data demonstrate that IL-4 uniquely prevents TGF-- induced expression of the adhesion receptors CD49a and CD103 that are required for CD8+ TRM persistence within peripheral tissues. In parallel, in vivo studies reveal that exposure of CD8+ T cells to IL-4 decreases both their expression of CD103 as well as their accumulation within skin. Based on these preliminary data, we propose to extend these studies using a mouse model of allergic asthma to test the novel hypothesis that Th2 cytokines impair lung CD8+ TRM formation, persistence and defense against respiratory infection. Specifically, we propose to: 1) Determine the impact of a Th2-type microenvironment on lung CD8+ TRM formation/persistence, as well as on the phenotypic stability of established CD8+ TRM; and 2) Determine the consequence of IL-4 on lung CD8+ TRM-mediated protective immunity to influenza infection.