TBX21, also known as T-bet, is a crucial transcription factor that plays a vital role in coordinating the type 1 immune response. It is involved in multiple biological processes and has been associated with various disease-related pathways [1,2,3,4,5,8].

In colorectal cancer, TBX21 expression is decreased compared to normal tissue, and is negatively correlated with TNM stages. Ectopic expression of TBX21 inhibits cell proliferation, promotes apoptosis, and suppresses metastasis both in vitro and in vivo, via ARHGAP29/RSK/GSK3β-dependent and MYCT1/ZO-1 signaling-dependent manners [1,7]. In microsatellite-stable colorectal cancer, Fusobacterium nucleatum can induce Tbx21 promoter H3K27 acetylation and expression in CD8+ T cells, and TBX21 transcriptionally represses PD-1, alleviating CD8+ T cell exhaustion and promoting effector function, thus facilitating anti-PD-1 therapy [2]. In CMS1 subtype colorectal cancer, high TBX21 expression and low methylation are associated with a survival advantage, and it may be regulated by the TP53/P53 pathway [3].

In late-onset Alzheimer's disease, TBX21 mRNA expression is elevated in the leukocytes of peripheral blood, and the TT genotype of rs41515744 plays a protective role [4]. In periapical lesions, the TBX21-1993 T allele and TC/CC genotypes predispose to Th1-type immune response development in vitro and influence immune response polarization in vivo [5]. In Asian seabass, tbx21 is associated with resistance against viral nervous necrosis (VNN), with overexpression reducing NNV replication [6].

In obesity, ablation of Tbx21 specifically in B cells reduces inflammatory cytokines and macrophages in adipose tissue, ameliorating metabolic symptoms [8]. In Japanese patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), PTCL-TBX21 shows different clinicopathological features and better prognosis compared to PTCL-GATA3 [9].

In conclusion, TBX21 is essential for the type 1 immune response and is involved in numerous disease-related processes. Studies, including those using in vivo models (although not all are KO/CKO mouse models), have revealed its role in cancers, neurodegenerative diseases, inflammatory conditions, and infectious diseases in fish, providing insights into potential therapeutic targets and disease mechanisms.