Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan.
Department of Otorhinolaryngology, Head and Neck Surgery, Akita University Graduate School of Medicine, Akita, Japan.
J Exp Med. 2023 Jul 3;220(7). doi: 10.1084/jem.20222005. Epub 2023 Apr 10.
While group-2 innate lymphoid cells (ILC2s) are highly proliferative in allergic inflammation, the removal of overactivated ILC2s in allergic diseases has not been investigated. We previously showed that chronic airway allergy induces "exhausted-like" dysfunctional ILC2s expressing T cell immunoreceptor with Ig and ITIM domains (TIGIT). However, the physiological relevance of these cells in chronic allergy remains elusive. To precisely identify and monitor TIGIT+ ILC2s, we generated TIGIT lineage tracer mice. Chronic allergy stably induced TIGIT+ ILC2s, which were highly activated, apoptotic, and were quickly removed from sites of chronic allergy. Transcripts from coding genes were globally suppressed in the cells, possibly due to reduced chromatin accessibility. Cell death in TIGIT+ ILC2s was enhanced by interactions with CD155 expressed on macrophages, whereas genetic ablation of Tigit or blockade by anti-TIGIT antagonistic antibodies promoted ILC2 survival, thereby deteriorating chronic allergic inflammation. Our work demonstrates that TIGIT shifts the fate of ILC2s toward activation-induced cell death, which could present a new therapeutic target for chronic allergies.
虽然 2 型固有淋巴细胞 (ILC2) 在过敏炎症中高度增殖，但在过敏疾病中尚未研究过度激活的 ILC2 的清除。我们之前曾表明，慢性气道过敏会诱导表达 T 细胞免疫受体 Ig 和 ITIM 结构域 (TIGIT) 的“衰竭样”功能失调的 ILC2。然而，这些细胞在慢性过敏中的生理相关性仍然难以捉摸。为了准确识别和监测 TIGIT+ ILC2，我们生成了 TIGIT 谱系示踪小鼠。慢性过敏稳定地诱导了 TIGIT+ ILC2，这些细胞高度激活、凋亡，并迅速从慢性过敏部位清除。编码基因的转录物在细胞中被全面抑制，可能是由于染色质可及性降低所致。TIGIT+ ILC2 与巨噬细胞上表达的 CD155 相互作用会增强细胞死亡，而 Tigit 的基因缺失或抗 TIGIT 拮抗抗体的阻断则促进了 ILC2 的存活，从而恶化了慢性过敏炎症。我们的工作表明，TIGIT 将 ILC2 的命运转向激活诱导的细胞死亡，这可能为慢性过敏提供一个新的治疗靶点。
