Sepsis is a systemic infection that enhances host vulnerability to secondary infections normally controlled by T cells. Using CLP sepsis model, we observed that sepsis induces apoptosis of circulating memory CD8 T-cells (T_CIRCM) and diminishes their effector functions, leading to impaired CD8 T-cell mediated protection to systemic pathogen re-infection. In the context of localized re-infections, tissue resident memory CD8 T-cells (T_RM) provide robust protection in a variety of infectious models. T_RM rapidly ‘sense’ infection in non-lymphoid tissues and ‘alarm’ the host by enhancing immune cell recruitment to the site of the infection to accelerate pathogen clearance. Here, we show that compared to pathogen-specific T_CIRCM, sepsis does not invoke significant numerical decline of Vaccinia virus induced skin-T_RM keeping their effector functions (e.g., Ag-dependent IFN-γ production) intact. IFN-γ-mediated recruitment of immune cells to the site of localized infection was, however, reduced in CLP hosts despite T_RM maintaining their ‘sensing and alarming’ functions. The capacity of memory CD8 T-cells in the septic environment to respond to inflammatory cues and arrive to the site of secondary infection/antigen exposure remained normal suggesting T-cell-extrinsic factors contributed to the observed lesion. Mechanistically, we showed that IFN-γ produced rapidly during sepsis-induced cytokine storm leads to reduced IFN-γR1 expression on vascular endothelium. As a consequence, decreased expression of adhesion molecules and/or chemokines (VCAM1 and CXCL9) on skin endothelial cells in response to T_RM-derived IFN-γ was observed, leading to sub-optimal bystander-recruitment of effector cells and increased susceptibility to pathogen re-encounter. Importantly, as visualized by intravital 2-photon microscopy, exogenous administration of CXCL9/10 was sufficient to correct sepsis-induced impairments in recruitment of effector cells at the localized site of T_RM antigen recognition. Thus, sepsis has the capacity to alter skin T_RM anamnestic responses without directly impacting T_RM number and/or function, an observation that helps to further define the immunoparalysis phase in sepsis survivors.

脓毒症是一种全身感染，可增强宿主对通常由T细胞控制的继发感染的脆弱性。使用CLP脓毒症模型，我们观察到脓毒症可诱导循环记忆CD8 T细胞（T _CIRCM）凋亡并减弱其效应功能，从而导致CD8 T细胞介导的对系统性病原体再感染的保护受损。在局部再感染的情况下，组织常驻记忆CD8 T细胞（T _RM）在多种感染模型中提供强大的保护。T _RM通过增强免疫细胞募集到感染部位来加速病原体清除，从而在非淋巴组织中迅速“感知”感染，并“警告”宿主。在这里，我们证明了与病原体特异性T _CIRCM相比，败血症没有引起痘苗病毒诱导的皮肤-T _RM的显着数值下降，从而保持其效应子功能（例如，Ag依赖性IFN-γ产生）保持完整。尽管有T _RM，但在CLP宿主中，IFN-γ介导的免疫细胞募集到局部感染的部位却减少了保持其“感应和报警”功能。在脓毒症环境中，记忆CD8 T细胞对炎症信号作出反应并到达继发感染/抗原暴露部位的能力仍然正常，这表明T细胞外源性因素促成了观察到的病变。从机制上讲，我们显示在脓毒症诱导的细胞因子风暴期间迅速产生的IFN-γ导致血管内皮上IFN-γR1的表达降低。因此，响应T _RM，皮肤内皮细胞上粘附分子和/或趋化因子（VCAM1和CXCL9）的表达降低。观察到源自IFN-γ的细胞，导致效应细胞的次优招募，并增加了对病原体再遇到的敏感性。重要的是，通过活体2光子显微镜观察，CXCL9 / 10的外源给药足以纠正败血症诱导的_TRM抗原识别定位位点效应细胞募集的损伤。因此，脓毒症具有改变皮肤T _RM记忆消除反应的能力，而没有直接影响T _RM数量和/或功能，这一观察有助于进一步确定脓毒症幸存者的免疫麻痹阶段。