Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, 3000, Australia.
Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia.
Nat Commun. 2024 Nov 14;15(1):9872. doi: 10.1038/s41467-024-54074-8.
Superantigens (sAgs) are bacterial virulence factors that induce a state of immune hyperactivation by forming a bridge between certain subsets of T cell receptor (TCR) β chains on T lymphocytes, and class II major histocompatibility complex (MHC-II) molecules; this cross-linking leads to indiscriminate T cell activation, cytokine storm and toxic shock. Here we show that sAg exposure drives the preferential expansion of naive and central memory T cell subsets, but not effector or resident memory T cells, which instead, hyper release pro-inflammatory cytokines. A targeted therapeutic approach to minimise cytokine release by effector memory T cells attenuated sAg-induced cytokine release. Irrespective of antigen experience, sAg activation does not render mature T cells permanently dysfunctional, and full restoration of effector function is observed following a transient and reversible anergy. Moreover, we show that in the face of sAg induced immune hyperactivation, an intact bacterium-specific CD4 T cell response can be mounted.
超抗原（sAg）是细菌的毒力因子，通过在 T 淋巴细胞上的 T 细胞受体（TCR）β 链的某些亚类与 II 类主要组织相容性复合体（MHC-II）分子之间形成桥联，诱导免疫过度激活；这种交联导致 T 细胞的非特异性激活、细胞因子风暴和中毒性休克。在这里，我们表明 sAg 暴露驱动幼稚和中央记忆 T 细胞亚群的优先扩增，但不驱动效应或驻留记忆 T 细胞，相反，它们过度释放促炎细胞因子。通过针对效应记忆 T 细胞的靶向治疗方法来最小化细胞因子的释放，可以减轻 sAg 诱导的细胞因子释放。无论抗原经验如何，sAg 激活都不会使成熟 T 细胞永久失能，并且在短暂和可逆的失能后观察到效应功能的完全恢复。此外，我们表明，在面对 sAg 诱导的免疫过度激活时，可以建立完整的细菌特异性 CD4 T 细胞反应。
