Pattern recognition receptors (PRRs) expressed in antigen-presenting cells are thought to shape pathogen-specific immunity by inducing secretion of costimulatory cytokines during T-cell activation, yet data to support this notion in vivo are scarce. Here, we show that the cytosolic PRR Nod-like Receptor CARD 4 (NLRC4) suppresses, rather than facilitates, effector and memory CD4⁺ T-cell responses against Salmonella in mice. NLRC4 negatively regulates immunological memory by preventing delayed activation of the cytosolic PRR NLR pyrin domain 3 (NLRP3) that would otherwise amplify the production of cytokines important for the generation of Th1 immunity such as intereukin-18. Consistent with a role for NLRC4 in memory immunity, primary challenge with Salmonella expressing flagellin modified to largely evade NLRC4 recognition notably increases protection against lethal rechallenge. This finding suggests flagellin modification to reduce NLRC4 activation enhances protective immunity, which could have important implications for vaccine development against flagellated microbial pathogens.

在抗原呈递细胞中表达的模式识别受体 (PRR) 被认为通过在 T 细胞激活期间诱导共刺激细胞因子的分泌来塑造病原体特异性免疫，但在体内支持这一观点的数据很少。在这里，我们显示细胞溶质 PRR Nod 样受体 CARD 4 (NLRC4) 抑制而不是促进效应和记忆 CD4 ⁺ T 细胞对小鼠沙门氏菌的反应。NLRC4 通过阻止细胞溶质 PRR NLR pyrin 结构域 3 (NLRP3) 的延迟激活来负调节免疫记忆，否则会放大对 Th1 免疫产生重要的细胞因子的产生，例如 intereukin-18。与 NLRC4 在记忆免疫中的作用一致，沙门氏菌的主要挑战表达经过修饰以在很大程度上逃避 NLRC4 识别的鞭毛蛋白显着增加了对致命再攻击的保护。这一发现表明，通过对鞭毛蛋白进行修饰以减少 NLRC4 的激活可以增强保护性免疫，这可能对开发针对有鞭毛的微生物病原体的疫苗具有重要意义。